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Li X, Hu Y, Aslanbeigi F. Genetic and epigenetic alterations in night shift nurses with breast cancer: a narrative review. Cancer Cell Int 2025; 25:20. [PMID: 39833897 PMCID: PMC11749300 DOI: 10.1186/s12935-025-03649-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
This narrative review explores the link between breast cancer and night shift work in nurses, focusing on genetic and epigenetic factors. Breast cancer disproportionately affects women globally, and night shift work is increasingly recognized as a potential risk factor. Nurses who work consecutive overnight shifts face elevated risks due to disruptions in their circadian rhythms. Studies suggest that working six or more successive night shifts, particularly over five years or more, may increase breast cancer risk. This review hypothesizes that disruptions in the sleep-wake cycle, such as changes in melatonin production and telomere length, could contribute to breast cancer susceptibility. Currently, there is limited genetic evidence to support this hypothesis. However, it is plausible that genetic and epigenetic alterations, including changes in genes like ER and HER2, may heighten the risk for night shift nurses. These alterations may involve variations in telomere length, DNA methylation, and disruptions in critical breast cancer-related genes. We highlight various genetic and epigenetic changes that may influence this increased susceptibility. Further research is needed to explore the underlying mechanisms and contributing factors in this association.
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Affiliation(s)
- Xia Li
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, Zhe'jiang, China
| | - Yingyu Hu
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, Zhe'jiang, China.
| | - Fatemeh Aslanbeigi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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2
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Eremici I, Borlea A, Dumitru C, Stoian D. Breast Cancer Risk Factors among Women with Solid Breast Lesions. Clin Pract 2024; 14:473-485. [PMID: 38525715 PMCID: PMC10961805 DOI: 10.3390/clinpract14020036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/10/2024] [Accepted: 03/12/2024] [Indexed: 03/26/2024] Open
Abstract
BACKGROUND Breast cancer is the most frequent malignancy in women worldwide and one of the most curable cancers if diagnosed at an early stage. Female patients presenting solid breast lesions are greatly predisposed to breast cancer development, and as such, effective screening of high-risk patients is valuable in early-stage breast cancer detection. OBJECTIVES The aim of our study was to identify the most relevant demographic, reproductive and lifestyle risk factors for breast cancer among women with solid breast lesions living in western Romania, namely the urban region consisting of Timisoara and the rural surrounding regions. METHODS From January 2017 to December 2021, 1161 patients with solid breast lesions, as detected by sonoelastography, were divided into two groups: patients with benign lesions (1019, 87.77%) and patients with malignant nodules (142, 12.23%). The malignancy group was confirmed by a histopathological result. Variables including age, BMI, menarche, menopause, years of exposure to estrogen, number of births, breastfeeding period, use of oral combined contraceptives, smoker status, family medical history and living area (rural-urban) were recorded. RESULTS It was evidenced by our study that the main risk factors for malignancy were elevated age (OR = 1.07, 95% CI 1.05-1.08), BMI (OR = 1.06, 95% CI 1.02-1.10), living area (rural) (OR = 1.86, 95% CI 1.13-2.85) and family medical history (negative) (OR 3.13, 95% CI 1.43-8.29). The other proposed risk factors were not found to be statistically significant. CONCLUSIONS Age and BMI were observed to be the most significant factors for breast cancer risk increase, followed by living in a rural area. A family history of breast cancer was shown to be inversely correlated with cancer risk increase.
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Affiliation(s)
- Ivana Eremici
- PhD School, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Andreea Borlea
- Department of Internal Medicine II, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Catalin Dumitru
- Obstetrics and Gynecology Department, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Dana Stoian
- Department of Internal Medicine II, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Gedon J, Wehrend A, Kessler M. Ovariectomy reduces the risk of tumour development and influences the histologic continuum in canine mammary tumours. Vet Comp Oncol 2021; 20:476-483. [PMID: 34913241 DOI: 10.1111/vco.12793] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 12/13/2021] [Indexed: 11/28/2022]
Abstract
Influence of neutering on canine mammary tumorigenesis has been a source of vivid discussion over the last decades. The purpose of this retrospective study was to describe the association between neuter status, tumour size and degree of malignancy in a large population of 625 female dogs with altogether 1459 removed mammary tumours (MTs). MT-bearing dogs were predominantly intact (80.3%) and intact dogs were overrepresented in the tumour population compared to the control group of >19 000 females (p < .0001). Multiple MT occurred in 340 patients (54.4%) and were significantly more common in intact dogs (57.8% vs. 40.7% spayed). Neutered dogs were not only significantly more likely to have a malignant MT (p < .0001) but were significantly more often affected by more aggressive tumour subtypes (p < .0001). Positive correlation between increasing tumour size and increasingly malignant phenotype was slightly stronger in spayed (rs = .217; p = .021) compared to intact (rs = .179; p = .0003) patients. After ovariectomy, progression from benign to malignant occurs in smaller size tumours, as MT ≥2 cm in diameter were malignant in 86.9% of the spayed patients, compared to 62.0% in intact patients (p = .0002). Intact bitches have a higher risk for MTs and tumour multiplicity. MTs in neutered females are more often malignant and belong to more aggressive subtypes compared to MTs in intact dogs. In neutered bitches, histologic progression from benign to malignant and further along the cancer progression continuum occurs at smaller tumour sizes.
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Affiliation(s)
- Julia Gedon
- Small Animal Clinic Hofheim, Hofheim am Taunus, Germany
| | - Axel Wehrend
- Clinic for Obstetrics, Gynaecology and Andrology of Large and Small Animals, Justus-Liebig-University, Giessen, Germany
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Zuo Q, Band S, Kesavadas M, Madak Erdogan Z. Obesity and Postmenopausal Hormone Receptor-positive Breast Cancer: Epidemiology and Mechanisms. Endocrinology 2021; 162:6370080. [PMID: 34519778 DOI: 10.1210/endocr/bqab195] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Indexed: 12/11/2022]
Abstract
Obesity is a potential risk for several cancers, including postmenopausal, hormone dependent breast cancers. In this review, we summarize recent studies on the impact of obesity on postmenopausal women's health and discuss several mechanisms that were proposed to increase the risk of breast carcinogenesis.
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Affiliation(s)
- Qianying Zuo
- Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Shoham Band
- Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Mrinali Kesavadas
- Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Zeynep Madak Erdogan
- Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA
- Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA
- Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA
- Department of Biomedical and Translational Sciences, Carle Illinois, College of Medicine, University of Illinois, Urbana-Champaign, Urbana, IL, USA
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5
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Farvid MS, Sidahmed E, Spence ND, Mante Angua K, Rosner BA, Barnett JB. Consumption of red meat and processed meat and cancer incidence: a systematic review and meta-analysis of prospective studies. Eur J Epidemiol 2021; 36:937-951. [PMID: 34455534 DOI: 10.1007/s10654-021-00741-9] [Citation(s) in RCA: 193] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/15/2021] [Indexed: 02/06/2023]
Abstract
Red meat and processed meat consumption has been hypothesized to increase risk of cancer, but the evidence is inconsistent. We performed a systematic review and meta-analysis of prospective studies to summarize the evidence of associations between consumption of red meat (unprocessed), processed meat, and total red and processed meat with the incidence of various cancer types. We searched in MEDLINE and EMBASE databases through December 2020. Using a random-effect meta-analysis, we calculated the pooled relative risk (RR) and 95% confidence intervals (CI) of the highest versus the lowest category of red meat, processed meat, and total red and processed meat consumption in relation to incidence of various cancers. We identified 148 published articles. Red meat consumption was significantly associated with greater risk of breast cancer (RR = 1.09; 95% CI = 1.03-1.15), endometrial cancer (RR = 1.25; 95% CI = 1.01-1.56), colorectal cancer (RR = 1.10; 95% CI = 1.03-1.17), colon cancer (RR = 1.17; 95% CI = 1.09-1.25), rectal cancer (RR = 1.22; 95% CI = 1.01-1.46), lung cancer (RR = 1.26; 95% CI = 1.09-1.44), and hepatocellular carcinoma (RR = 1.22; 95% CI = 1.01-1.46). Processed meat consumption was significantly associated with a 6% greater breast cancer risk, an 18% greater colorectal cancer risk, a 21% greater colon cancer risk, a 22% greater rectal cancer risk, and a 12% greater lung cancer risk. Total red and processed meat consumption was significantly associated with greater risk of colorectal cancer (RR = 1.17; 95% CI = 1.08-1.26), colon cancer (RR = 1.21; 95% CI = 1.09-1.34), rectal cancer (RR = 1.26; 95% CI = 1.09-1.45), lung cancer (RR = 1.20; 95% CI = 1.09-1.33), and renal cell cancer (RR = 1.19; 95% CI = 1.04-1.37). This comprehensive systematic review and meta-analysis study showed that high red meat intake was positively associated with risk of breast cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, lung cancer, and hepatocellular carcinoma, and high processed meat intake was positively associated with risk of breast, colorectal, colon, rectal, and lung cancers. Higher risk of colorectal, colon, rectal, lung, and renal cell cancers were also observed with high total red and processed meat consumption.
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Affiliation(s)
- Maryam S Farvid
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Elkhansa Sidahmed
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Nicholas D Spence
- Department of Sociology and Department of Health and Society, University of Toronto, Toronto, ON, Canada
| | | | - Bernard A Rosner
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Junaidah B Barnett
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Fujii T, Ogasawara M, Kamishikiryo J, Morita T. β-Estradiol Enhanced Secretion of Lipoprotein Lipase from Mouse Mammary Tumor FM3A Cells. Biol Pharm Bull 2021; 43:1407-1412. [PMID: 32879215 DOI: 10.1248/bpb.b20-00408] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The role of β-estradiol (E2) in lipoprotein metabolism in mammary tumors is unclear, therefore, we investigated the effect of E2 on the secretion of lipoprotein lipase (LPL) from mouse mammary tumor FM3A cells. E2-treated cells increased the secretion of active LPL from FM3A cells in a time- and dose-dependent manner. Activity of mitogen-activated protein kinase (MAPK) was increased in the tumor cells treated with E2, and enhanced secretion of LPL was suppressed by MAPK kinase 1/2 inhibitor, PD98059, extracellular signal-regulated kinase (ERK) 1/2 inhibitor, FR180204, p38 MAPK inhibitor, SB202190, and phosphatidyl inositol 3-kinase (PI3K) inhibitor, LY294002. In addition, the effect of E2 on LPL secretion was markedly suppressed by an inhibitor of mammalian target of rapamycin complex (mTORC) 1 and 2, KU0063794, but were not by a mTORC1 inhibitor, rapamycin. Furthermore, a small interfering RNA (siRNA)-mediated decrease in the expression of rapamycin-insensitive companion of mTOR (Rictor), a pivotal component of mTORC2, suppressed secretion of LPL by E2. These results suggest that the stimulatory secretion of LPL by E2 from the tumor cells is closely associated with an activation of mTORC2 rather than mTORC1 possibly via the MAPK cascade.
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Affiliation(s)
- Tomoyasu Fujii
- Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
| | - Mizuho Ogasawara
- Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University.,Department of Pharmacy, Kochi Health Sciences Center
| | - Jun Kamishikiryo
- Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
| | - Tetsuo Morita
- Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
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Calaf GM. Role of organophosphorous pesticides and acetylcholine in breast carcinogenesis. Semin Cancer Biol 2021; 76:206-217. [PMID: 33766648 DOI: 10.1016/j.semcancer.2021.03.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/18/2021] [Indexed: 12/16/2022]
Abstract
Breast cancer is the leading cause of cancer-related death in women worldwide. Several studies have addressed the association between cancer in humans and agricultural pesticide exposure. Evidence indicates that exposure to organophosphorous pesticides such as parathion and malathion occurs as a result of occupational factors since they are extensively used to control insects. On the other hand, estrogens have been considered beneficial to the organism; however, epidemiological studies have pointed out an increased breast cancer risk in both humans and animals. Experimental female rat mammary gland cancer models were developed after exposure to parathion, malathion, eserine, an acetylcholinesterase inhibitor, and estrogen allowing the analysis of the signs of carcinogenicity as alteration of cell proliferation, receptor expression, genomic instability, and cell metabolism in vivo and in vitro. Thus, pesticides increased proliferative ducts followed by ductal carcinoma; and 17β-estradiol increased proliferative lobules followed by lobular carcinomas. The combination of both pesticides and either eserine or estrogen induced tumors with both types of structures followed by mammary gland tumors and metastasis to the lung and kidneys after 240 days of a 5-day treatment. Studies also showed that these pesticides and eserine decreased three to five times the acetylcholinesterase activity in the serum compared to controls whereas terminal end buds increased in number, being inhibited by atropine. Genomic instability was analyzed in such tissues (mp53, CYP1A2, c-myc, c-fos, ERα, M2R) and pesticides increased protein expression that was stimulated by estrogens but inhibited by atropine. Eserine also transformed the epithelium of the rat mammary gland in the presence of estrogen and increased the number of terminal end buds after treatment inducing mammary carcinomas. Then, enzymatic digestion of such structures gave rise to cells with increased DNA synthesis and induced anchorage independence. Thus, there were changes in the epithelium of the mammary gland influencing breast carcinogenesis. Furthermore, these substances and acetylcholine also showed the signs of carcinogenicity in vitro as cell proliferation, receptor expression (ERα, ErbB2, M2R), genomic instability (c-myc, mp53, ERα, M2R), and cell metabolism. A unique cellular model is also presented here based on the use of MCF-10 F, a non-tumorigenic cell line that represents a valuable clinically translatable experimental approach that identifies mechanistic links for pesticides and estrogen as suspect human carcinogenic agents.
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Affiliation(s)
- Gloria M Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica, 1000000, Chile; Center for Radiological Research, Columbia University Medical Center, New York, NY, 10032, USA.
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Subia B, Dahiya UR, Mishra S, Ayache J, Casquillas GV, Caballero D, Reis RL, Kundu SC. Breast tumor-on-chip models: From disease modeling to personalized drug screening. J Control Release 2021; 331:103-120. [PMID: 33417986 PMCID: PMC8172385 DOI: 10.1016/j.jconrel.2020.12.057] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 02/06/2023]
Abstract
Breast cancer is one of the leading causes of mortality worldwide being the most common cancer among women. Despite the significant progress obtained during the past years in the understanding of breast cancer pathophysiology, women continue to die from it. Novel tools and technologies are needed to develop better diagnostic and therapeutic approaches, and to better understand the molecular and cellular players involved in the progression of this disease. Typical methods employed by the pharmaceutical industry and laboratories to investigate breast cancer etiology and evaluate the efficiency of new therapeutic compounds are still based on traditional tissue culture flasks and animal models, which have certain limitations. Recently, tumor-on-chip technology emerged as a new generation of in vitro disease model to investigate the physiopathology of tumors and predict the efficiency of drugs in a native-like microenvironment. These microfluidic systems reproduce the functional units and composition of human organs and tissues, and importantly, the rheological properties of the native scenario, enabling precise control over fluid flow or local gradients. Herein, we review the most recent works related to breast tumor-on-chip for disease modeling and drug screening applications. Finally, we critically discuss the future applications of this emerging technology in breast cancer therapeutics and drug development.
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Affiliation(s)
- Bano Subia
- Elvesys Microfluidics Innovation Centre, Paris 75011, France..
| | | | - Sarita Mishra
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India..
| | - Jessica Ayache
- Elvesys Microfluidics Innovation Centre, Paris 75011, France..
| | | | - David Caballero
- 3B's Research Group, I3Bs-Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Barco, Guimarãaes 4805-017, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4805-017, Braga/Guimarães, Portugal.
| | - Rui L Reis
- 3B's Research Group, I3Bs-Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Barco, Guimarãaes 4805-017, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4805-017, Braga/Guimarães, Portugal.
| | - Subhas C Kundu
- 3B's Research Group, I3Bs-Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Barco, Guimarãaes 4805-017, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4805-017, Braga/Guimarães, Portugal.
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9
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Curcumin, oxidative stress, and breast cancer. Cancer 2021. [DOI: 10.1016/b978-0-12-819547-5.00032-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Parmar HS, Nayak A, Gavel PK, Jha HC, Bhagwat S, Sharma R. Cross Talk between COVID-19 and Breast Cancer. Curr Cancer Drug Targets 2021; 21:575-600. [PMID: 33593260 DOI: 10.2174/1568009621666210216102236] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/17/2020] [Accepted: 12/26/2020] [Indexed: 01/08/2023]
Abstract
Cancer patients are more susceptible to COVID-19; however, the prevalence of COVID-19 in different types of cancer is still inconsistent and inconclusive. Here, we delineate the intricate relationship between breast cancer and COVID-19. Breast cancer and COVID-19 share the involvement of common comorbidities, hormonal signalling pathways, gender differences, rennin- angiotensin system (RAS), angiotensin-converting enzyme-2 (ACE-2), transmembrane protease serine 2 (TMPRSS2) and dipeptidyl peptidase-IV (DPP-IV). We also shed light on the possible effects of therapeutic modalities of COVID-19 on breast cancer outcomes. Briefly, we conclude that breast cancer patients are more susceptible to COVID-19 in comparison with their normal counterparts. Women are more resistant to the occurrence and severity of COVID-19. Increased expressions of ACE2 and TMPRSS2 are correlated with occurrence and severity of COVID-19, but higher expression of ACE2 and lower expression of TMPRSS2 are prognostic markers for overall disease free survival in breast cancer. The ACE2 inhibitors and ibuprofen therapies for COVID-19 treatment may aggravate the clinical condition of breast cancer patients through chemo-resistance and metastasis. Most of the available therapeutic modalities for COVID-19 were also found to exert positive effects on breast cancer outcomes. Besides drugs in clinical trend, TMPRSS2 inhibitors, estrogen supplementation, androgen deprivation and DPP-IV inhibitors may also be used to treat breast cancer patients infected with SARS-CoV-2. However, drug-drug interactions suggest that some of the drugs used for the treatment of COVID-19 may modulate the drug metabolism of anticancer therapies which may lead to adverse drug reaction events.
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Affiliation(s)
| | - Aakruti Nayak
- School of Biotechnology, Devi Ahilya University, Indore-452001. M.P., India
| | - Pramod Kumar Gavel
- Department of Chemical Sciences, IIT, Indore, Simrol, Indore, M.P., India
| | - Hem Chandra Jha
- Department of Bioscience and Bioengineering, IIT, Indore, Simrol, Indore, M.P., India
| | - Shivani Bhagwat
- Suraksha Diagnostics Pvt. Ltd., Newtown, Rajarhat, Kolkata-West Bengal, India
| | - Rajesh Sharma
- School of Pharmacy, Devi Ahilya University, Indore-452001., M.P., India
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Imbalances in the disposition of estrogen and naphthalene in breast cancer patients: a potential biomarker of breast cancer risk. Sci Rep 2020; 10:11773. [PMID: 32678225 PMCID: PMC7366907 DOI: 10.1038/s41598-020-68814-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/29/2020] [Indexed: 12/21/2022] Open
Abstract
Elevation of naphthoquinones and estrogen quinones, which are reactive metabolites of naphthalene and estrogen, is thought to be an important indicator of naphthalene- and estrogen-induced carcinogenesis. We compared background levels of naphthalene and estrogen quinone-derived adducts in serum albumin (Alb) from 143 women with breast cancer and 119 healthy controls. Cysteinyl adducts of naphthoquinones, including 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ), and estrogen quinones, including estrogen-2,3-quinones (E2-2,3-Q) and estrogen-3,4-quinones (E2-3,4-Q), were characterized after adduct cleavage. Levels of estrogen quinones and naphthoquinones were positively correlated in healthy controls, but not in breast cancer patients (p < 0.05). Compared with controls, levels of 1,2-NPQ and E2-3,4-Q were elevated by two- to ten-fold in cancer patients (p < 0.001). To explore the correlation between estrogen- and naphthalene-derived quinone adducts and disease status, we performed linear discriminant analysis of the ratio of 1,2-NPQ-Alb to (1,2-NPQ-Alb plus 1,4-NPQ-Alb) versus the ratio of E2-3,4-Q-2-S-Alb to (E2-2,3-Q-4-S-Alb plus E2-3,4-Q-2-S-Alb) in patients and controls. These two groups were separable using albumin adducts of estrogen quinones and naphthoquinones, with 99.6% overall correct classification rate (overall accuracy). The findings of this study suggest that differences in the disposition of estrogen and naphthalene, and the subsequent elevation of cumulative E2-3,4-Q and 1,2-NPQ may serve as biomarkers of breast cancer risk.
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12
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Relationship of Serum Progesterone and Progesterone Metabolites with Mammographic Breast Density and Terminal Ductal Lobular Unit Involution among Women Undergoing Diagnostic Breast Biopsy. J Clin Med 2020; 9:jcm9010245. [PMID: 31963437 PMCID: PMC7019918 DOI: 10.3390/jcm9010245] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/06/2020] [Accepted: 01/09/2020] [Indexed: 12/21/2022] Open
Abstract
The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40–65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.
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De Amicis F, Chiodo C, Morelli C, Casaburi I, Marsico S, Bruno R, Sisci D, Andò S, Lanzino M. AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells. BMC Cancer 2019; 19:1038. [PMID: 31684907 PMCID: PMC6829973 DOI: 10.1186/s12885-019-6262-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 10/15/2019] [Indexed: 12/16/2022] Open
Abstract
Background Androgens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis. Methods Cell counting by trypan blu exclusion was used to study androgen effect on estrogen-dependent breast tumor growth. Quantitative Real Time RT–PCR, western blotting, transient transfection, protein immunoprecipitation and chromatin immunoprecipitation assays were carried out to investigate how androgen treatment and/or androgen receptor overexpression influences the functional interaction between the steroid receptor coactivator AIB1 and the estrogen- or androgen receptor which, in turn affects the estrogen-induced cyclin D1 gene expression in MCF-7 breast cancer cells. Data were analyzed by ANOVA. Results Here we demonstrated, in estrogen receptor α (ERα)-positive breast cancer cells, an androgen-dependent mechanism through which ligand-activated androgen receptor (AR) decreases estradiol-induced cyclin D1 protein, mRNA and gene promoter activity. These effects involve the competition between AR and ERα for the interaction with the steroid receptor coactivator AIB1, a limiting factor in the functional coupling of the ERα with the cyclin D1 promoter. Indeed, AIB1 overexpression is able to reverse the down-regulatory effects exerted by AR on ERα-mediated induction of cyclin D1 promoter activity. Co-immunoprecipitation studies indicated that the preferential interaction of AIB1 with ERα or AR depends on the intracellular expression levels of the two steroid receptors. In addition, ChIP analysis evidenced that androgen administration decreased E2-induced recruitment of AIB1 on the AP-1 site containing region of the cyclin D1 gene promoter. Conclusions Taken together all these data support the hypothesis that AIB1 sequestration by AR may be an effective mechanism to explain the reduction of estrogen-induced cyclin D1 gene activity. In estrogen-dependent breast cancer cell proliferation, these findings reinforce the possibility that targeting AR signalling may potentiate the effectiveness of anti-estrogen adjuvant therapies.
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Affiliation(s)
- Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
| | - Chiara Chiodo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
| | - Catia Morelli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
| | - Ivan Casaburi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
| | - Stefania Marsico
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
| | - Rosalinda Bruno
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
| | - Diego Sisci
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy.
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
| | - Marilena Lanzino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, CS, 87036, Arcavacata di Rende, Italy
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The estrogen effect; clinical and histopathological evidence of dichotomous influences in dogs with spontaneous mammary carcinomas. PLoS One 2019; 14:e0224504. [PMID: 31652293 PMCID: PMC6814212 DOI: 10.1371/journal.pone.0224504] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/10/2019] [Indexed: 11/21/2022] Open
Abstract
The purpose of this study was to investigate the associations and explore the relationships between hormonal factors (serum estrogen, estrogen receptors and ovariohysterectomy) and other clinical/histological prognostic factors and their impact on outcome in dogs with mammary carcinomas. Data from two separate prospective studies on dogs with spontaneous mammary carcinomas were used for this research. All dogs underwent standardized diagnostic testing, staging, surgery and follow-up examinations. Serum estrogen was analyzed by competitive enzyme immunoassay or radioimmunoassay, and tumor estrogen receptor (ER) expression was analyzed by immunohistochemistry. A total of 159 dogs were included; 130 were spayed and 29 remained. High serum estrogen was associated with an overall longer time to metastasis (p = 0.021). When stratifying based on spay group, the effect was only significant in spayed dogs, (p = 0.019). Positive tumor ER expression was also associated with a longer time to metastasis (p = 0.025), but similar to above, only in dogs that were spayed (p = 0.049). Further subgroup analysis revealed that high serum estrogen was significantly associated with improved survival in dogs with ER positive tumors, but only in spayed dogs (p = 0.0052). Interestingly, the effect of spaying was the opposite in dogs with ER negative tumors; here, intact dogs with high serum estrogen but ER negative tumors had a significantly longer time to metastasis (p = 0.036). Low serum estrogen was associated with increased risk for the development of non-mammary tumors in the post-operative period (p = 0.012). These results highlight the dual effect of estrogen in cancer: Estrogen acts as a pro-carcinogen in ER positive mammary tumors, but a may have a protective effect in ER negative tumors, potentially via non-receptor mechanisms. The latter is supported by the decreased risk for non-mammary tumors in dogs with high serum estrogen, and explains the increased incidence of certain non-mammary tumors in in dogs spayed at an early age.
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15
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de Oliveira HL, Pires BC, Teixeira LS, Dinali LAF, Simões NS, Borges WDS, Borges KB. Novel restricted access material combined to molecularly imprinted polymer for selective magnetic solid-phase extraction of estrogens from human urine. Microchem J 2019. [DOI: 10.1016/j.microc.2019.104043] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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16
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Lin PH, Yang HJ, Hsieh WC, Lin C, Chan YC, Wang YF, Yang YT, Lin KJ, Lin LS, Chen DR. Albumin and hemoglobin adducts of estrogen quinone as biomarkers for early detection of breast cancer. PLoS One 2018; 13:e0201241. [PMID: 30222738 PMCID: PMC6141067 DOI: 10.1371/journal.pone.0201241] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 07/11/2018] [Indexed: 12/21/2022] Open
Abstract
Cumulative estrogen concentration is an important determinant of the risk of developing breast cancer. Estrogen carcinogenesis is attributed to the combination of receptor-driven mitogenesis and DNA damage induced by quinonoid metabolites of estrogen. The present study was focused on developing an improved breast cancer prediction model using estrogen quinone-protein adduct concentrations. Blood samples from 152 breast cancer patients and 71 healthy women were collected, and albumin (Alb) and hemoglobin (Hb) adducts of estrogen-3,4-quinone and estrogen-2,3-quinone were extracted and evaluated as potential biomarkers of breast cancer. A multilayer perceptron (MLP) was used as the predictor model and the resultant prediction of breast cancer was more accurate than other existing detection methods. A MLP using the logarithm of the concentrations of the estrogen quinone-derived adducts (four input nodes, 10 hidden nodes, and one output node) was used to predict breast cancer risk with accuracy close to 100% and area under curve (AUC) close to one. The AUC value of one showed that both data sets were separable. We conclude that Alb and Hb adducts of estrogen quinones are promising biomarkers for the early detection of breast cancer.
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Affiliation(s)
- Po-Hsiung Lin
- Department of Environmental Engineering, National Chung Hsing University, South Dist., Taichung, Taiwan, R.O.C
| | - Hui-Ju Yang
- Department of Dermatology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
| | - Wei-Chung Hsieh
- Department of Internal Medicine, Da-Chien General Hospital, Miaoli, Taiwan, R.O.C
| | - Che Lin
- Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
| | - Ya-Chi Chan
- Cancer Research Center, Department of Research, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
| | - Yu-Fen Wang
- Cancer Research Center, Department of Research, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
| | - Yuan-Ting Yang
- Department of Pharmacy, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
| | - Kuo-Juei Lin
- Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Li-Sheng Lin
- Department of Breast Surgery, the Affiliated Hospital (Group) of Putian University, Putian, Fujian, China
| | - Dar-Ren Chen
- Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
- Cancer Research Center, Department of Research, Changhua Christian Hospital, Changhua, Taiwan, R.O.C
- School of Medicine, Chung Shan Medical University, South Dist., Taichung, Taiwan, R.O.C
- * E-mail:
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Oestrogen receptor-regulated glutathione S-transferase mu 3 expression attenuates hydrogen peroxide-induced cytotoxicity, which confers tamoxifen resistance on breast cancer cells. Breast Cancer Res Treat 2018; 172:45-59. [PMID: 30054830 DOI: 10.1007/s10549-018-4897-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 07/17/2018] [Indexed: 12/15/2022]
Abstract
PURPOSE Glutathione S-transferase mu 3 (GSTM3) is an enzyme involving in the detoxification of electrophilic compounds by conjugation with glutathione. Higher GSTM3 mRNA levels were reported in patients with ERα-positive breast cancer who received only tamoxifen therapy after surgery. Thus, this study aimed to clarify the oncogenic characteristics of GSTM3 in breast cancer and the mechanism of tamoxifen resistance. METHODS GSTM3 expression in human breast tumour tissues (n = 227) was analysed by RT-PCR and quantitative PCR. Western blot, promoter activity assays, and chromatin immunoprecipitation (ChIP) assays were used to investigate the mechanism of GSTM3 gene regulation. Hydrogen peroxide (H2O2)-induced cytotoxicity in breast cancer cells was detected by MTT assays and flow cytometry. The oncogenic characteristics of GSTM3 in MCF-7 cells were examined by siRNA knockdown in soft agar assays and a xenograft animal model. RESULTS GSTM3 mRNA was highly expressed in ER- and HER2-positive breast cancers. Moreover, patients who received adjuvant Herceptin had increased GSTM3 mRNA levels in tumour tissue. Oestrogen-activated GSTM3 gene expression through ERα-mediated recruitment of SP1, EP300, and AP-1 complexes. GSTM3-silenced MCF-7 cells were more sensitive to H2O2, with significantly inhibited proliferation and colony formation abilities. Tamoxifen-resistant (Tam-R) cells lacking GSTM3 showed enhanced sensitivity to H2O2, but this result was contrary to that obtained after short-term tamoxifen exposure. The animal model suggested that GSTM3 silencing might suppress the tumourigenic ability of MCF-7 cells and increase tumour cell apoptosis. CONCLUSIONS ROS production is one mechanism by which cancer drugs kill tumour cells, and according to our evidence, GSTM3 may play an important role in preventing breast cancer treatment-induced cellular cytotoxicity.
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Calaf GM, Urzua U, Termini L, Aguayo F. Oxidative stress in female cancers. Oncotarget 2018; 9:23824-23842. [PMID: 29805775 PMCID: PMC5955122 DOI: 10.18632/oncotarget.25323] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 04/06/2018] [Indexed: 12/16/2022] Open
Abstract
Breast, cervical and ovarian cancers are highly prevalent in women worldwide. Environmental, hormonal and viral-related factors are especially relevant in the development of these tumors. These factors are strongly related to oxidative stress (OS) through the generation of reactive oxygen species (ROS). The OS is caused by an imbalance in the redox status of the organism and is literally defined as "an imbalance between ROS generation and its detoxification by biological system leading to impairment of damage repair by cell/tissue". The multistep progression of cancer suggests that OS is involved in cancer initiation, promotion and progression. In this review, we described the role of OS and the interplay with environmental, host and viral factors related to breast, cervical and ovarian cancers initiation, promotion and progression. In addition, the role of the natural antioxidant compound curcumin and other compounds for breast, cervical and ovarian cancers prevention/treatment is discussed.
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Affiliation(s)
- Gloria M. Calaf
- Instituto de Alta Investigación (IAI), Universidad de Tarapacá, Arica, Chile
- Center for Radiological Research, Columbia University Medical Center, New York, NY, USA
| | - Ulises Urzua
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Lara Termini
- Instituto do Câncer do Estado de São Paulo, Centro de Investigação Translacional em Oncologia, Laboratório de Oncologia Experimental, São Paulo, SP, Brazil
| | - Francisco Aguayo
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile
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Abdul-Maksoud RS, Elsayed WS, Elsayed RS. The influence of glyoxalase 1 gene polymorphism on its expression at different stages of breast cancer in Egyptian women. Genes Cancer 2017; 8:799-807. [PMID: 29321821 PMCID: PMC5755725 DOI: 10.18632/genesandcancer.163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aim To assess the association of GLO1 C332C gene polymorphism with breast cancer risk at different stages of the disease and to investigate the effect of this gene polymorphism on its mRNA expression and enzyme activity. Methods GLO1 C332C gene polymorphism was analyzed by PCR-RFLP in 100 healthy controls and 200 patients with breast cancer (100 patients with stage I & II and 100 patients with stage III & IV). GLO1 mRNA expression was measured by real time PCR. Serum GLO1 enzyme activity was measured colorimetrically. Results GLO1 A allele was associated with increased risk of breast cancer [OR (95%CI)= 2.8(1.9-4.1), P < 0.001]. Its frequency was significantly higher among advanced stages of breast cancer compared with localized tumors (OR (95%CI)= 1.9(1.3-2.9), p < 0.001). GLO1 mRNA expression and enzyme activity were significantly higher in breast cancer patients compared to controls and they were much higher in the advanced stages of the disease (P < 0.001). Carriers of AA genotype showed higher GLO1 expression and enzyme activity compared with carriers of CC genotype. Conclusion GLO1 C332C SNP was associated with overexpression of GLO1 mRNA and higher enzyme activity in breast cancer patients suggesting its role in the development of breast cancer and its progression from localized to advanced.
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Affiliation(s)
| | - Walid Sh Elsayed
- Pathology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Rasha S Elsayed
- General Surgery Department, Faculty of Medicine, Zagazig University, Egypt
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20
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Zutz C, Wagener K, Yankova D, Eder S, Möstl E, Drillich M, Rychli K, Wagner M, Strauss J. A robust high-throughput fungal biosensor assay for the detection of estrogen activity. Steroids 2017; 126:57-65. [PMID: 28712952 DOI: 10.1016/j.steroids.2017.07.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/17/2017] [Accepted: 07/10/2017] [Indexed: 01/13/2023]
Abstract
Estrogenic active compounds are present in a variety of sources and may alter biological functions in vertebrates. Therefore, it is crucial to develop innovative analytical systems that allow us to screen a broad spectrum of matrices and deliver fast and reliable results. We present the adaptation and validation of a fungal biosensor for the detection of estrogen activity in cow derived samples and tested the clinical applicability for pregnancy diagnosis in 140 mares and 120 cows. As biosensor we used a previously engineered genetically modified strain of the filamentous fungus Aspergillus nidulans, which contains the human estrogen receptor alpha and a reporter construct, in which β-galactosidase gene expression is controlled by an estrogen-responsive-element. The estrogen response of the fungal biosensor was validated with blood, urine, feces, milk and saliva. All matrices were screened for estrogenic activity prior to and after chemical extraction and the results were compared to an enzyme immunoassay (EIA). The biosensor showed consistent results in milk, urine and feces, which were comparable to those of the EIA. In contrast to the EIA, no sample pre-treatment by chemical extraction was needed. For 17β-estradiol, the biosensor showed a limit of detection of 1ng/L. The validation of the biosensor for pregnancy diagnosis revealed a specificity of 100% and a sensitivity of more than 97%. In conclusion, we developed and validated a highly robust fungal biosensor for detection of estrogen activity, which is highly sensitive and economic as it allows analyzing in high-throughput formats without the necessity for organic solvents.
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Affiliation(s)
- Christoph Zutz
- Research Platform Bioactive Microbial Metabolites (BiMM), Bioresources and Technologies Campus Tulln, Konrad Lorenz Straße 24, 3430 Tulln, Austria; Institute of Milk Hygiene, Milk Technology and Food Science, Department of Farm Animal and Veterinary Public Health, Vetmeduni Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Karen Wagener
- University Clinic for Ruminants, Clinical Unit for Herd Health Management in Ruminants, Department for Farm Animals and Veterinary Public Health, Vetmeduni Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
| | - Desislava Yankova
- Research Platform Bioactive Microbial Metabolites (BiMM), Bioresources and Technologies Campus Tulln, Konrad Lorenz Straße 24, 3430 Tulln, Austria
| | - Stefanie Eder
- University Clinic for Ruminants, Clinical Unit for Herd Health Management in Ruminants, Department for Farm Animals and Veterinary Public Health, Vetmeduni Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Erich Möstl
- Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, Vetmeduni Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Marc Drillich
- University Clinic for Ruminants, Clinical Unit for Herd Health Management in Ruminants, Department for Farm Animals and Veterinary Public Health, Vetmeduni Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Kathrin Rychli
- Institute of Milk Hygiene, Milk Technology and Food Science, Department of Farm Animal and Veterinary Public Health, Vetmeduni Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Martin Wagner
- Institute of Milk Hygiene, Milk Technology and Food Science, Department of Farm Animal and Veterinary Public Health, Vetmeduni Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Joseph Strauss
- Research Platform Bioactive Microbial Metabolites (BiMM), Bioresources and Technologies Campus Tulln, Konrad Lorenz Straße 24, 3430 Tulln, Austria; Fungal Genetics and Genomics Unit, Department of Applied Genetics and Cell Biology, BOKU University of Natural Resources and Life Sciences Vienna, Konrad Lorenz Straße 24, 3430 Tulln, Austria
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Cavalieri EL, Rogan EG. Etiology and prevention of prevalent types of cancer. JOURNAL OF RARE DISEASES RESEARCH & TREATMENT 2017; 2:22-29. [PMID: 30854528 PMCID: PMC6404759 DOI: 10.29245/2572-9411/2017/3.1093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Endogenous estrogens become carcinogens when excessive catechol estrogen quinone metabolites are formed. Specifically, the catechol estrogen-3,4-quinones can react with DNA to produce a large amount of specific depurinating estrogen-DNA adducts, formed at the N-3 of Ade and N-7 of Gua. Loss of these adducts leaves apurinic sites in the DNA, which can generate subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of the depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from studies in vitro, in cell culture, in animal models and in human subjects. High levels of estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, and in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Two dietary supplements, N-acetylcysteine and resveratrol, complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these epithelial cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. Blocking initiation of cancer prevents promotion, progression and development of the disease. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.
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Affiliation(s)
- Ercole L. Cavalieri
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
- Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198-4388, USA
| | - Eleanor G. Rogan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
- Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198-4388, USA
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Cavalieri EL, Rogan EG, Zahid M. Critical depurinating DNA adducts: Estrogen adducts in the etiology and prevention of cancer and dopamine adducts in the etiology and prevention of Parkinson's disease. Int J Cancer 2017; 141:1078-1090. [PMID: 28388839 DOI: 10.1002/ijc.30728] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/23/2017] [Accepted: 03/17/2017] [Indexed: 01/19/2023]
Abstract
Endogenous estrogens become carcinogens when dangerous metabolites, the catechol estrogen quinones, are formed. In particular, the catechol estrogen-3,4-quinones can react with DNA to produce an excess of specific depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from various types of studies. High levels of depurinating estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, as well as in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Formation of analogous depurinating dopamine-DNA adducts is hypothesized to initiate Parkinson's disease by affecting dopaminergic neurons. Two dietary supplements, N-acetylcysteine and resveratrol complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. When initiation of cancer is blocked, promotion, progression and development of the disease cannot occur. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.
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Affiliation(s)
- Ercole L Cavalieri
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.,Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE
| | - Eleanor G Rogan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.,Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE
| | - Muhammad Zahid
- Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE
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23
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Lacazette E. A laboratory practical illustrating the use of the ChIP-qPCR method in a robust model: Estrogen receptor alpha immunoprecipitation using Mcf-7 culture cells. BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION : A BIMONTHLY PUBLICATION OF THE INTERNATIONAL UNION OF BIOCHEMISTRY AND MOLECULAR BIOLOGY 2017; 45:152-160. [PMID: 27666748 DOI: 10.1002/bmb.20999] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 05/26/2016] [Accepted: 06/10/2016] [Indexed: 06/06/2023]
Abstract
Chromatin immunoprecipitation followed by qPCR analysis (ChIP-qPCR) is a widely used technique to study gene expression. A large number of students in molecular biology and more generally in life sciences will be confronted with the use of this technique, which is quite difficult to set up and can lead to misinterpretation if not carefully managed. This article describes a four-session laboratory practical designed for Masters students to introduce this technique. During the practical, students work in pairs. They extract chromatin from MCF-7 culture cells stimulated or not by estrogens, then immunoprecipitate the transcription factor estrogen receptor alpha using an antibody directed against it. Students then measure the enrichment of promoter DNA target sequences from the chromatin that coprecipitates by qPCR. These are two estrogen responsive genes, pS2 (trefoil factor one) and PGR (the progesterone receptor). They learn how to analyze their ChIP-qPCR data by two methods: percent input and fold enrichment, and are taught about the interpretation limits of these two calculation methods. Thus, this practical is a good framework for an in-depth discussion of how this technique can be used to study gene expression and for raising awareness of the importance of careful interpretation of results. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(2):152-160, 2017.
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Affiliation(s)
- Eric Lacazette
- Cancer Research Center of Toulouse-UMR1037 Inserm, Université Toulouse III Paul Sabatier, Oncopole de Toulouse, 31037 Toulouse Cedex 1, France
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The Effect of Polymorphisms on the Ala 119 Ser Gene Cytochrome P450 1B1*2 on the Susceptibility of Iranian Women to Develop Breast Cancer. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcp.4042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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25
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Sampson JN, Falk RT, Schairer C, Moore SC, Fuhrman BJ, Dallal CM, Bauer DC, Dorgan JF, Shu XO, Zheng W, Brinton LA, Gail MH, Ziegler RG, Xu X, Hoover RN, Gierach GL. Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women. Cancer Res 2017; 77:918-925. [PMID: 28011624 PMCID: PMC5313342 DOI: 10.1158/0008-5472.can-16-1717] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 11/04/2016] [Accepted: 11/20/2016] [Indexed: 12/21/2022]
Abstract
Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. Cancer Res; 77(4); 918-25. ©2017 AACR.
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Affiliation(s)
- Joshua N Sampson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Roni T Falk
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Catherine Schairer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Steven C Moore
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Barbara J Fuhrman
- University of Arkansas for Medical Sciences, Fay W. Boozman College of Public Health, Little Rock, Arkansas
| | - Cher M Dallal
- University of Maryland School of Public Health, College Park, Maryland
| | - Douglas C Bauer
- University of California at San Francisco, San Francisco, California
| | - Joanne F Dorgan
- University of Maryland School of Medicine, Baltimore, Maryland
| | - Xiao-Ou Shu
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Wei Zheng
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Louise A Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Mitchell H Gail
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Regina G Ziegler
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Xia Xu
- Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Robert N Hoover
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Gretchen L Gierach
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
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Ball LJ, Palesh O, Kriegsfeld LJ. The Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis. Endocr Rev 2016; 37:450-466. [PMID: 27712099 PMCID: PMC5045494 DOI: 10.1210/er.2015-1133] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health.
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Affiliation(s)
- Lonnele J Ball
- Department of Psychology (L.J.B., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, California 94720; and Department of Psychiatry and Behavioral Sciences (O.P.), Stanford University School of Medicine, Stanford, California 94305
| | - Oxana Palesh
- Department of Psychology (L.J.B., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, California 94720; and Department of Psychiatry and Behavioral Sciences (O.P.), Stanford University School of Medicine, Stanford, California 94305
| | - Lance J Kriegsfeld
- Department of Psychology (L.J.B., L.J.K.) and The Helen Wills Neuroscience Institute (L.J.K.), University of California, Berkeley, California 94720; and Department of Psychiatry and Behavioral Sciences (O.P.), Stanford University School of Medicine, Stanford, California 94305
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27
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Duration of ovarian hormone exposure and gynecological cancer risk in Korean women: the Korean Heart Study. Cancer Epidemiol 2016; 41:1-7. [DOI: 10.1016/j.canep.2016.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 12/03/2015] [Accepted: 01/04/2016] [Indexed: 11/15/2022]
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Sanchez MIGL, Shearwood AMJ, Chia T, Davies SMK, Rackham O, Filipovska A. Estrogen-mediated regulation of mitochondrial gene expression. Mol Endocrinol 2016; 29:14-27. [PMID: 25375021 DOI: 10.1210/me.2014-1077] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Estrogens, in particular 17β-estradiol, are well-known regulators of essential cellular functions; however, discrepancies remain over the mechanisms by which they act on mitochondria. Here we propose a novel mechanism for the direct regulation of mitochondrial gene expression by estrogen under metabolic stress. We show that in serum-depleted medium, estrogen stimulates a rapid relocation of estrogen receptor-α to mitochondria, in which it elicits a cellular response, resulting in an increase in mitochondrial RNA abundance. Mitochondrial RNA levels are regulated through the association of estrogen receptor-α with 17β-hydroxysteroid dehydrogenase 10, a multifunctional protein involved in steroid metabolism that is also a core subunit of the mitochondrial ribonuclease P complex responsible for the cleavage of mitochondrial polycistronic transcripts. Processing of mitochondrial transcripts affects mitochondrial gene expression by controlling the levels of mature RNAs available for translation. This work provides the first mechanism linking RNA processing and estrogen activation in mitochondrial gene expression and underscores the coordinated response between the nucleus and mitochondria in response to stress.
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Affiliation(s)
- Maria I G Lopez Sanchez
- Harry Perkins Institute of Medical Research and Centre for Medical Research (M.I.G.L.S., A.-M.J.S., T.-S.C., S.M.K.D., O.R., A.F.), Queen Elizabeth II Medical Centre, Nedlands, and School of Chemistry and Biochemistry (O.R., A.F.), The University of Western Australia, Crawley, Western Australia 6009, Australia
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29
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Chen L, Lu W, Fang L, Xiong H, Wu X, Zhang M, Wu S, Yu D. Association between L55M polymorphism in Paraoxonase 1 and cancer risk: a meta-analysis based on 21 studies. Onco Targets Ther 2016; 9:1151-8. [PMID: 27019599 PMCID: PMC4786067 DOI: 10.2147/ott.s96990] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
L55M polymorphism in Paraoxonase 1 (PON1) has been regarded as a risk factor for many cancer types. Nevertheless, the results remain controversial and inconclusive. We therefore performed a meta-analysis of all eligible case–control studies to evaluate the association between L55M polymorphism and cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. Finally, a total of 5,627 cases and 6,390 controls, arising from 21 case–control studies, were enrolled in our study. Significant associations between PON1-L55M polymorphism and overall cancer risk were identified in all genetic models. In the stratified analyses by cancer type, PON1-L55M polymorphism was a risk factor for breast cancer in all genetic models, prostate cancer in the heterozygote model (ML vs LL: OR =1.304, 95% CI =1.049–1.620, Pheterogeneity=0.067), and ovarian cancer in the recessive model (MM vs ML/LL: OR =1.526, 95% CI =1.110–2.097, Pheterogeneity=0.464). Similarly, an increased risk was also identified for the Caucasian population in the heterozygote comparison and homozygote models, and hospital-based controls in all genetic models. To sum up, our study suggests that the PON1-L55M allele increased the risk of cancer. Future well-designed studies with larger sample sizes are warranted to further verify these findings.
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Affiliation(s)
- Lei Chen
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Wei Lu
- Department of Urology, Anhui Medical University Graduate School, Hefei, Anhui, People's Republic of China
| | - Lu Fang
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Hu Xiong
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, People's Republic of China
| | - Xun Wu
- Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China
| | - Meng Zhang
- Department of Urology, Anhui Medical University Graduate School, Hefei, Anhui, People's Republic of China
| | - Song Wu
- Department of Urology, Anhui Medical University Graduate School, Hefei, Anhui, People's Republic of China
| | - Dexin Yu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China
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30
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Cavalieri EL, Rogan EG. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention. Clin Transl Med 2016; 5:12. [PMID: 26979321 PMCID: PMC4792821 DOI: 10.1186/s40169-016-0088-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 02/28/2016] [Indexed: 02/15/2023] Open
Abstract
Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma. Depurinating estrogen-DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts could prevent the initiation of human cancer. The dietary supplements N-acetylcysteine and resveratrol inhibit formation of estrogen-DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer. Graphical abstract Major metabolic pathway in cancer initiation by estrogens.
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Affiliation(s)
- Ercole L. Cavalieri
- />Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE USA
- />Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE USA
| | - Eleanor G. Rogan
- />Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE USA
- />Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE USA
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31
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van Mackelenbergh MT, Lindner CM, Heilmann T, Alkatout I, Elessawy M, Mundhenke C, Maass N, Schem C. Impact of Histopathological Factors, Patient History and Therapeutic Variables on Recurrence-free Survival after Ductal Carcinoma in Situ: 8-Year Follow-up and Questionnaire Survey. Geburtshilfe Frauenheilkd 2016; 76:46-52. [PMID: 26855440 DOI: 10.1055/s-0041-110805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Introduction: Ductal carcinoma in situ (DCIS) is a premalignant lesion of the glandular component of the breast and a precursor lesion of invasive breast cancer. In recent decades the incidence of DCIS has risen continuously, mainly because of more extensive screening and more advanced diagnostic procedures. There is an increasing need for evidence-based treatment guidelines which will protect patients as far as possible from recurrence or invasive cancer but also from overtreatment. This retrospective single-center clinical trial analyzed recurrence-free survival times, rates of invasive and non-invasive events, and the impact of patient history, histopathological variables and therapeutic factors on recurrence-free survival times. Material and Methods: A total of 200 patients who underwent surgery between 2000 and 2007 for pure DCIS were included in the study. As part of follow-up a questionnaire was sent to patients and their respective gynecologists. Results: In the follow-up period, 12.5 % (n = 25) of the 200 patients had recurrence (invasive or non-invasive event). Menopausal status, tumor grade and tumor size were significantly associated with recurrence. Low-grade DCIS was significantly more often hormone receptor-positive than high-grade DCIS. Patients who had postoperative radiotherapy significantly more often also received endocrine drug treatment. There was a significant association between younger patient age and drug treatment. The study found that in the investigated cohort, premenopausal women had a significantly shorter recurrence-free time compared to postmenopausal women. Conclusion: This paper summarizes the current literature on DCIS. There is a need for more prospective clinical trials to improve the prognosis of premenopausal women with large and hormone receptor-positive DCIS.
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Affiliation(s)
- M T van Mackelenbergh
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
| | - C M Lindner
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
| | - T Heilmann
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
| | - I Alkatout
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
| | - M Elessawy
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
| | - C Mundhenke
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
| | - N Maass
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
| | - C Schem
- Obstetrics and Gynecology, University Hospital Center Schleswig-Holstein, Campus Kiel, Kiel
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Abstract
The final therapeutic effect of a drug candidate, which is directed to a specific molecular target strongly depends on its absorption, distribution, metabolism and excretion (ADME). The disruption of at least one element of ADME may result in serious drug resistance. In this work we described the role of one element of this resistance: phase II metabolism with UDP-glucuronosyltransferases (UGTs). UGT function is the transformation of their substrates into more polar metabolites, which are better substrates for the ABC transporters, MDR1, MRP and BCRP, than the native drug. UGT-mediated drug resistance can be associated with (i) inherent overexpression of the enzyme, named intrinsic drug resistance or (ii) induced expression of the enzyme, named acquired drug resistance observed when enzyme expression is induced by the drug or other factors, as food-derived compounds. Very often this induction occurs via ligand binding receptors including AhR (aryl hydrocarbon receptor) PXR (pregnane X receptor), or other transcription factors. The effect of UGT dependent resistance is strengthened by coordinate action and also a coordinate regulation of the expression of UGTs and ABC transporters. This coupling of UGT and multidrug resistance proteins has been intensively studied, particularly in the case of antitumor treatment, when this resistance is "improved" by differences in UGT expression between tumor and healthy tissue. Multidrug resistance coordinated with glucuronidation has also been described here for drugs used in the management of epilepsy, psychiatric diseases, HIV infections, hypertension and hypercholesterolemia. Proposals to reverse UGT-mediated drug resistance should consider the endogenous functions of UGT.
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Affiliation(s)
- Zofia Mazerska
- Gdańsk University of Technology, Chemical Faculty, Department of Pharmaceutical Technology and Biochemistry, 80-233 Gdańsk, Poland
| | - Anna Mróz
- Gdańsk University of Technology, Chemical Faculty, Department of Pharmaceutical Technology and Biochemistry, 80-233 Gdańsk, Poland
| | - Monika Pawłowska
- Gdańsk University of Technology, Chemical Faculty, Department of Pharmaceutical Technology and Biochemistry, 80-233 Gdańsk, Poland
| | - Ewa Augustin
- Gdańsk University of Technology, Chemical Faculty, Department of Pharmaceutical Technology and Biochemistry, 80-233 Gdańsk, Poland.
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Wang ZY, Yin L. Estrogen receptor alpha-36 (ER-α36): A new player in human breast cancer. Mol Cell Endocrinol 2015; 418 Pt 3:193-206. [PMID: 25917453 DOI: 10.1016/j.mce.2015.04.017] [Citation(s) in RCA: 125] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 04/20/2015] [Accepted: 04/20/2015] [Indexed: 01/16/2023]
Abstract
Prevailing wisdom is that estrogen receptor (ER)-α mediated genomic estrogen signaling is responsible for estrogen-stimulated cell proliferation and development of ER-positive breast cancer. However, accumulating evidence indicates that another estrogen signaling pathway, non-genomic or rapid estrogen signaling, also plays an important role in mitogenic estrogen signaling. Previously, our laboratory cloned a 36 kDa variant of ER-α, ER-α36, and found that ER-α36 is mainly expressed in the cytoplasm and at the plasma membrane. ER-α36 mediates rapid estrogen signaling and inhibits genomic estrogen signaling. In this review, we review and update the biological function of ER-α36 in ER-positive and -negative breast cancer, breast cancer stem/progenitor cells and tamoxifen resistance, potential interaction and cross-talk of ER-α36 with other ERs and growth factor receptors, and intracellular pathways of ER-α36-mediated rapid estrogen signaling. The potential function and underlying mechanism of ER-α in development of ER-positive breast cancer will also be discussed.
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Affiliation(s)
- Zhao-Yi Wang
- Department of Medical Microbiology & Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA.
| | - Li Yin
- Department of Medical Microbiology & Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA
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34
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Parodi DA, Greenfield M, Evans C, Chichura A, Alpaugh A, Williams J, Martin MB. Alteration of mammary gland development and gene expression by in utero exposure to arsenic. Reprod Toxicol 2015; 54:66-75. [PMID: 25543096 PMCID: PMC4465030 DOI: 10.1016/j.reprotox.2014.12.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 12/07/2014] [Accepted: 12/16/2014] [Indexed: 01/02/2023]
Abstract
Early life exposure to estrogens and estrogen like contaminants in the environment is thought to contribute to the early onset of puberty and consequently increases the risk of developing breast cancer in the exposed female. The results of this study show that in utero exposure to the metalloestrogen arsenite altered mammary gland development prior to its effect on puberty onset. In the prepubertal gland, in utero exposure resulted in an increase in the number of mammosphere-forming cells and an increase in branching, epithelial cells, and density. In the postpubertal gland, in utero exposure resulted in the overexpression of estrogen receptor-alpha (ERα) that was due to the increased and altered response of the ERα transcripts derived from exons O and OT to estradiol. These results suggest that, in addition to advancing puberty onset, in utero exposure to arsenite alters the pre- and postpubertal development of the mammary gland and possibly, the risk of developing breast cancer.
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Affiliation(s)
- Daniela A Parodi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA
| | - Morgan Greenfield
- Department of Oncology, Georgetown University, Washington, DC 20007, USA
| | - Claire Evans
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA
| | - Anna Chichura
- Department of Oncology, Georgetown University, Washington, DC 20007, USA
| | - Alexandra Alpaugh
- Department of Oncology, Georgetown University, Washington, DC 20007, USA
| | - James Williams
- Department of Oncology, Georgetown University, Washington, DC 20007, USA
| | - Mary Beth Martin
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA; Department of Oncology, Georgetown University, Washington, DC 20007, USA.
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35
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Al-Amri FA, Saeedi MY, Al-Tahan FM, Ali AM, Alomary SA, Arafa M, Ibrahim AK, Kassim KA. Breast cancer correlates in a cohort of breast screening program participants in Riyadh, KSA. J Egypt Natl Canc Inst 2015; 27:77-82. [PMID: 25935858 DOI: 10.1016/j.jnci.2015.04.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 04/06/2015] [Accepted: 04/07/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Breast cancer is the first cancer among females in the Kingdom of Saudi Arabia, accounting for 27.4% of all newly diagnosed female cancers in 2010. There are several risk factors affecting the incidence of breast cancer where some factors influence the risk more than the others. AIM We aimed to identify the different risk factors related to breast cancer among females participating in the breast-screening program in Riyadh, KSA. METHODS Based on data from phase-I of the breast-screening program, a case-control study was conducted on women living in Riyadh, KSA. A sample of 349 women (58 cases and 290 controls) was recruited to examine the different breast cancer correlates. Multivariate regression model was built to investigate the most important risk factors. RESULTS The mean age of cases was 48.5±7.1 years. Age at marriage, number of pregnancy, age at menopause, oral contraceptive pills, breast feeding and family history of breast cancer in first-degree relative were identified as the most important correlates among the studied cohort. CONCLUSIONS The findings of the current work suggested that age at marriage, age at menopause ⩾50 years and 1st degree family history of breast cancer were risk factors for breast cancer, while, age at menopause <50 years, number of pregnancies and practicing breast feeding were protective factors against breast cancer. There was no effect of body mass index or physical inactivity. Further studies are needed to explore the hereditary, familial and genetic background risk factors in Saudi population.
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Affiliation(s)
- Fahad A Al-Amri
- Ministry of Health, Deputy Ministry for Public Health, Assistant Deputy for Primary Health Care, Riyadh, Saudi Arabia
| | - Mohammed Y Saeedi
- Ministry of Health, Deputy Ministry for Public Health, Assistant Deputy for Primary Health Care, Riyadh, Saudi Arabia
| | - Fatina M Al-Tahan
- Ministry of Health, Deputy Ministry for Public Health, Assistant Deputy for Primary Health Care, Riyadh, Saudi Arabia
| | - Arwa M Ali
- King Khalid University Hospitals, Medical Oncology Department, King Saud University, Saudi Arabia; Medical Oncology Department, South Egypt Cancer Institute, Assiut University, Asyut, Egypt
| | - Shaker A Alomary
- Ministry of Health, Deputy Ministry for Public Health, Assistant Deputy for Primary Health Care, Riyadh, Saudi Arabia
| | - Mostafa Arafa
- Community Medicine Department, King Saud University, Saudi Arabia
| | - Ahmed K Ibrahim
- Public Health & Community Medicine School, Faculty of Medicine, Assiut University, Asyut, Egypt.
| | - Kassim A Kassim
- Ministry of Health, Deputy Ministry for Public Health, Assistant Deputy for Primary Health Care, Riyadh, Saudi Arabia
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Patki M, Salazar MD, Trumbly R, Ratnam M. Differential effects of estrogen-dependent transactivation vs. transrepression by the estrogen receptor on invasiveness of HER2 overexpressing breast cancer cells. Biochem Biophys Res Commun 2015; 457:404-11. [PMID: 25582774 DOI: 10.1016/j.bbrc.2015.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 01/05/2015] [Indexed: 02/03/2023]
Abstract
Estrogen (E2) supports breast cancer cell growth but suppresses invasiveness and both actions are antagonized by anti-estrogens. As a consequence, anti-estrogen treatment may increase the invasive potential of estrogen receptor (ER)+ tumor cell sub-populations that are endocrine resistant due to HER2 amplification. Either transactivation or transrepression by E2/ER could lead to both up- and down-regulation of many genes. Inhibition of the transactivation function of ER is adequate to inhibit E2-dependent growth. However, the impact of inhibiting E2-dependent transactivation vs. transrepression by ER on regulation of invasiveness by E2 is less clear. Here we dissect the roles of ER-mediated transactivation and transrepression in the regulation of invasiveness of ER+/HER2+ breast cancer cells by E2. Knocking down the general ER co-activators CBP and p300 prevented activation by E2 of its classical target genes but did not interfere with the ability of E2 to repress its direct target genes known to support invasiveness and tumor progression; there was also no effect on invasiveness or the ability of E2 to regulate invasiveness. On the other hand, overexpression of a co-repressor binding site mutant of ER (L372R) prevented E2-dependent transrepression but not transactivation. The mutant ER abrogated the ability of E2 to suppress invasiveness. E2 can partially down-regulate HER2 but knocking down HER2 below E2-regulated levels did not affect invasiveness or the ability of E2 to regulate invasiveness, although it did inhibit growth. Therefore, in ER+/HER2+ cells, the E2-dependent transrepression by ER rather than its transactivation function is critical for regulation of invasiveness and this is independent of HER2 regulation by E2. The findings suggest that selective inhibitors of transactivation by ER may be more beneficial in reducing tumor progression than conventional anti-estrogens that also antagonize E2-dependent transrepression.
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Affiliation(s)
- Mugdha Patki
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, 4100 John R., Detroit, MI 48201, USA; Department of Biochemistry and Cancer Biology, University Medical Center, Toledo, OH 43614, USA
| | - Marcela d'alincourt Salazar
- Department of Biochemistry and Cancer Biology, University Medical Center, Toledo, OH 43614, USA; Division of Translational Research, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Robert Trumbly
- Department of Biochemistry and Cancer Biology, University Medical Center, Toledo, OH 43614, USA
| | - Manohar Ratnam
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, 4100 John R., Detroit, MI 48201, USA.
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Jesionowski AM, Gabriel SM, Rich JD, Schroeder JR. Failure of pesticides to alter migration of cancerous and non-cancerous breast cell lines in vitro. Toxicol Res (Camb) 2015. [DOI: 10.1039/c4tx00098f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Organochlorine pesticides are routinely used in agricultural processes across the United States.
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Affiliation(s)
| | | | - J. D. Rich
- Department of Biology
- Millikin University
- Decatur
- USA
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38
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McCaskill ML, Rogan E, Thomas RD. Diallyl sulfide inhibits diethylstilbestrol induced DNA damage in human breast epithelial cells (MCF-10A). Steroids 2014; 92:96-100. [PMID: 25278253 PMCID: PMC4426958 DOI: 10.1016/j.steroids.2014.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 07/22/2014] [Accepted: 09/18/2014] [Indexed: 11/24/2022]
Abstract
Breast cancer is the second leading cause of cancer deaths in women in the United States. Diethylstilbestrol (DES) is a synthetic estrogen that has been shown to cause cancer in animals and humans, altering cell viability as well as inducing DNA damage. Diallyl sulfide (DAS) is a garlic organosulfide that has been shown to inhibit both the initiation and promotion phases of cancer in vivo and in vitro, as well as reduce the risk of cancer in epidemiological studies. MCF-10A cells, regarded as a normal breast epithelial cell line, were treated with varying concentrations of DES, DAS or various dose combinations of DES and DAS concomitantly, and assessed for cell viability, DNA strand breaks, and lipid peroxidation. DES (10μM) in combination with 1, 10, or 100μM DAS resulted in a 31%, 34%, or 36% respective increase in cell viability compared to the DES treatment alone, after 24h. At the same time point, 1, 10, and 100μM DAS were all effective in significantly reducing DES (100μM)-induced strand breaks to near that of the vehicle control. Additionally, 1μM DAS was effective in significantly reducing DES (100μM)-induced lipid peroxidation after 3h. The results of this research suggest that DAS is effective in recovering cell viability, attenuating DNA strand breaks, and decreasing lipid peroxidation in MCF-10A cells.
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Affiliation(s)
- Michael L McCaskill
- Pharmacology/Toxicology Department, Basic Pharmaceutical Sciences Division, College of Pharmacy and Pharmaceutical Science, Florida A&M University, Tallahassee, FL 32307, United States; Global Environmental Health Sciences, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, United States.
| | - Eleanor Rogan
- Environmental Agricultural and Occupational Health Department, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, United States.
| | - Ronald D Thomas
- Pharmacology/Toxicology Department, Basic Pharmaceutical Sciences Department, College of Pharmacy and Pharmaceutical Science, Florida A&M University, Tallahassee, FL 32307, United States
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39
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Castro GD, Castro JA. Alcohol drinking and mammary cancer: Pathogenesis and potential dietary preventive alternatives. World J Clin Oncol 2014; 5:713-29. [PMID: 25300769 PMCID: PMC4129535 DOI: 10.5306/wjco.v5.i4.713] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/21/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is associated with an increased risk of breast cancer, increasing linearly even with a moderate consumption and irrespectively of the type of alcoholic beverage. It shows no dependency from other risk factors like menopausal status, oral contraceptives, hormone replacement therapy, or genetic history of breast cancer. The precise mechanism for the effect of drinking alcohol in mammary cancer promotion is still far from being established. Studies by our laboratory suggest that acetaldehyde produced in situ and accumulated in mammary tissue because of poor detoxicating mechanisms might play a role in mutational and promotional events. Additional studies indicated the production of reactive oxygen species accompanied of decreases in vitamin E and GSH contents and of glutathione transferase activity. The resulting oxidative stress might also play a relevant role in several stages of the carcinogenic process. There are reported in literature studies showing that plasmatic levels of estrogens significantly increased after alcohol drinking and that the breast cancer risk is higher in receptor ER-positive individuals. Estrogens are known that they may produce breast cancer by actions on ER and also as chemical carcinogens, as a consequence of their oxidation leading to reactive metabolites. In this review we introduce our working hypothesis integrating the acetaldehyde and the oxidative stress effects with those involving increased estrogen levels. We also analyze potential preventive actions that might be accessible. There remains the fact that alcohol drinking is just one of the avoidable causes of breast cancer and that, at present, the suggested acceptable dose for prevention of this risk is of one drink per day.
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40
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Equol elicits estrogenic activities via PI3K/akt pathway in the estrogen receptor-positive MCF-7 cells. Mol Cell Toxicol 2014. [DOI: 10.1007/s13273-014-0032-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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41
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Emori MM, Drapkin R. The hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis. Reprod Biol Endocrinol 2014; 12:60. [PMID: 24997727 PMCID: PMC4105128 DOI: 10.1186/1477-7827-12-60] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 06/27/2014] [Indexed: 12/21/2022] Open
Abstract
Ovulation has long been associated with an increased risk in ovarian cancer, yet the underlying molecular mechanisms remain obscure. Two aspects of ovulation have been linked to ovarian cancer pathogenesis. The first is the impact of repetitive tissue injury and repair that occurs with each ovulatory event. The second is the release of follicular fluid that accompanies the follicular rupture and its effect on the ovarian and fallopian tube epithelial cells. Hormones are an important component of follicular fluid, which transiently bathes the ovarian surface and fallopian tube epithelium during ovulation. Much work has been done exploring the role of hormones in fertility, but some, such as estrogen, have also been implicated in the pathogenesis of ovarian and other cancers. Understanding the role of hormones within follicular fluid, as well as how they are altered in disorders which increase ovarian cancer risk, will enhance our ability to assess risk and develop preventative strategies. This review provides an in depth discussion of the logistics of using and studying follicular fluid in ovarian cancer research, and discusses the fluctuations in follicular fluid hormone levels during normal physiological processes versus conditions that increase ovarian cancer risk.
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Affiliation(s)
- Megan M Emori
- Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| | - Ronny Drapkin
- Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
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Systemic identification of estrogen-regulated genes in breast cancer cells through cap analysis of gene expression mapping. Biochem Biophys Res Commun 2014; 447:531-6. [PMID: 24746470 DOI: 10.1016/j.bbrc.2014.04.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Accepted: 04/07/2014] [Indexed: 11/23/2022]
Abstract
To explore the estrogen-regulated genes genome-widely in breast cancer, cap analysis of gene expression (CAGE) sequencing was performed in MCF-7 cells under estrogen treatment. Estrogen-regulated expressional changes were found in 1537 CAGE tag clusters (TCs) (⩾1.5 or ⩽0.66-folds). Among them, 15 TCs were situated in the vicinity of (⩽10 kb) reported estrogen receptor-binding sites. Knockdown experiments of the 15 TC-associated genes demonstrated that the genes such as RAMP3, ISOC1 and GPRC5C potentially regulate the growth or migration of MCF-7 cells. These results suggest that CAGE sequencing will reveal novel estrogen target genes in breast cancer.
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Cavalieri E, Rogan E. The molecular etiology and prevention of estrogen-initiated cancers: Ockham's Razor: Pluralitas non est ponenda sine necessitate. Plurality should not be posited without necessity. Mol Aspects Med 2014; 36:1-55. [PMID: 23994691 PMCID: PMC3938998 DOI: 10.1016/j.mam.2013.08.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/05/2013] [Accepted: 08/06/2013] [Indexed: 12/22/2022]
Abstract
Elucidation of estrogen carcinogenesis required a few fundamental discoveries made by studying the mechanism of carcinogenesis of polycyclic aromatic hydrocarbons (PAH). The two major mechanisms of metabolic activation of PAH involve formation of radical cations and diol epoxides as ultimate carcinogenic metabolites. These intermediates react with DNA to yield two types of adducts: stable adducts that remain in DNA unless removed by repair and depurinating adducts that are lost from DNA by cleavage of the glycosyl bond between the purine base and deoxyribose. The potent carcinogenic PAH benzo[a]pyrene, dibenzo[a,l]pyrene, 7,12-dimethylbenz[a]anthracene and 3-methylcholanthrene predominantly form depurinating DNA adducts, leaving apurinic sites in the DNA that generate cancer-initiating mutations. This was discovered by correlation between the depurinating adducts formed in mouse skin by treatment with benzo[a]pyrene, dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]anthracene and the site of mutations in the Harvey-ras oncogene in mouse skin papillomas initiated by one of these PAH. By applying some of these fundamental discoveries in PAH studies to estrogen carcinogenesis, the natural estrogens estrone (E1) and estradiol (E2) were found to be mutagenic and carcinogenic through formation of the depurinating estrogen-DNA adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. These adducts are generated by reaction of catechol estrogen quinones with DNA, analogously to the DNA adducts obtained from the catechol quinones of benzene, naphthalene, and the synthetic estrogens diethylstilbestrol and hexestrol. This is a weak mechanism of cancer initiation. Normally, estrogen metabolism is balanced and few estrogen-DNA adducts are formed. When estrogen metabolism becomes unbalanced, more catechol estrogen quinones are generated, resulting in higher levels of estrogen-DNA adducts, which can be used as biomarkers of unbalanced estrogen metabolism and, thus, cancer risk. The ratio of estrogen-DNA adducts to estrogen metabolites and conjugates has repeatedly been found to be significantly higher in women at high risk for breast cancer, compared to women at normal risk. These results indicate that formation of estrogen-DNA adducts is a critical factor in the etiology of breast cancer. Significantly higher adduct ratios have been observed in women with breast, thyroid or ovarian cancer. In the women with ovarian cancer, single nucleotide polymorphisms in the genes for two enzymes involved in estrogen metabolism indicate risk for ovarian cancer. When polymorphisms produce high activity cytochrome P450 1B1, an activating enzyme, and low activity catechol-O-methyltransferase, a protective enzyme, in the same woman, she is almost six times more likely to have ovarian cancer. These results indicate that formation of estrogen-DNA adducts is a critical factor in the etiology of ovarian cancer. Significantly higher ratios of estrogen-DNA adducts to estrogen metabolites and conjugates have also been observed in men with prostate cancer or non-Hodgkin lymphoma, compared to healthy men without cancer. These results also support a critical role of estrogen-DNA adducts in the initiation of cancer. Starting from the perspective that unbalanced estrogen metabolism can lead to increased formation of catechol estrogen quinones, their reaction with DNA to form adducts, and generation of cancer-initiating mutations, inhibition of estrogen-DNA adduct formation would be an effective approach to preventing a variety of human cancers. The dietary supplements resveratrol and N-acetylcysteine can act as preventing cancer agents by keeping estrogen metabolism balanced. These two compounds can reduce the formation of catechol estrogen quinones and/or their reaction with DNA. Therefore, resveratrol and N-acetylcysteine provide a widely applicable, inexpensive approach to preventing many of the prevalent types of human cancer.
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Affiliation(s)
- Ercole Cavalieri
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA; Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, 984388 Nebraska Medical Center, Omaha, NE 68198-4388, USA.
| | - Eleanor Rogan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA; Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, 984388 Nebraska Medical Center, Omaha, NE 68198-4388, USA.
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Hemachandra LPMP, Patel H, Chandrasena REP, Choi J, Piyankarage SC, Wang S, Wang Y, Thayer EN, Scism RA, Michalsen BT, Xiong R, Siklos MI, Bolton JL, Thatcher GRJ. SERMs attenuate estrogen-induced malignant transformation of human mammary epithelial cells by upregulating detoxification of oxidative metabolites. Cancer Prev Res (Phila) 2014; 7:505-15. [PMID: 24598415 DOI: 10.1158/1940-6207.capr-13-0296] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER) and to chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Nontumorigenic MCF-10A human breast epithelial cells are classified as ER(-) and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERM), in use for breast cancer chemoprevention and for postmenopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular reactive oxygen species (ROS), and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of phase II rather than phase I metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of phase II metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs.
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Affiliation(s)
- L P Madhubhani P Hemachandra
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612.
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Wen CJ, Wu LX, Fu LJ, Shen DY, Zhang X, Zhang YW, Yu J, Zhou HH. Preferential Induction of CYP1A1 over CYP1B1 in Human Breast Cancer MCF-7 Cells after Exposure to Berberine. Asian Pac J Cancer Prev 2014; 15:495-9. [DOI: 10.7314/apjcp.2014.15.1.495] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Lin C, Chen DR, Wang SL, Hsieh WC, Yu WF, Wang TW, Tsai CH, Wei HH, Tsuang BJ, Lin PH. Cumulative body burdens of polycyclic aromatic hydrocarbons associated with estrogen bioactivation in pregnant women: protein adducts as biomarkers of exposure. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART A, TOXIC/HAZARDOUS SUBSTANCES & ENVIRONMENTAL ENGINEERING 2014; 49:634-640. [PMID: 24521408 DOI: 10.1080/10934529.2014.865416] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
The objective of this research was to simultaneously analyze protein adducts of quinonoid metabolites of naphthalene and endogenous estrogen in serum albumin (Alb) derived from healthy pregnant women in Taiwan and to explore the correlations among them. The isomeric forms of cysteinyl adducts of naphthoquinones, including 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) as well as estrogen quinones, including estrogen-2,3-quinones (E2-2,3-Q) and estrogen-3,4-quinones (E2-3,4-Q), are characterized after adduct cleavage. Results showed that the median levels of cysteinyl adducts of 1,2-NPQ and 1,4-NPQ on serum albumin were 249-390 and 16.0-24.8 pmol g(-1), respectively. Logged levels of 1,2-NPQ-Alb were correlated with logged levels of 1,4-NPQ-Alb (correlation coefficient r = 0.551, P < 0.001). Cysteinyl adducts of E2-2,3-Q-1-S-Alb, E2-2,3-Q-4-S-Alb, and E2-3,4-Q-2-S-Alb were detected in all subjects with median levels at 275-435, 162-288, and 197-254 pmol g(-1), respectively. We also found a positive relationship between logged levels of E2-2,3-Q-4-S-Alb and those of E2-3,4-Q-2-S-Alb (r = 0.770, P < 0.001).We noticed that median levels of E2-2,3-Q-derived adducts (E2-2,3-Q-1-S-Alb plus E2-2,3-Q-4-S-Alb) in pregnant women were greater than those of E2-3,4-Q-2-S-Alb (∼2-3-fold). Taken together, this evidence lends further support to the theme that cumulative concentration of E2-3,4-Q is a significant predictor of the risk of breast cancer. Furthermore, we noticed that levels of 1,2-NPQ-Alb are positively associated with levels of E2-3,4-Q-2-S-Alb (r = 0.522, P < 0.001) and those of E2-2,3-Q-4-S-Alb (r = 0.484, P < 0.001). Overall, this evidence suggests that environmental exposure to polycyclic aromatic hydrocarbons may modulate estrogen homeostasis and enhance the production of reactive quinone species of endogenous estrogen in humans.
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Affiliation(s)
- Che Lin
- a Comprehensive Breast Cancer Center, Changhua Christian Hospital , Changhua , Taiwan
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Yang L, Zahid M, Liao Y, Rogan EG, Cavalieri EL, Davidson NE, Yager JD, Visvanathan K, Groopman JD, Kensler TW. Reduced formation of depurinating estrogen-DNA adducts by sulforaphane or KEAP1 disruption in human mammary epithelial MCF-10A cells. Carcinogenesis 2013; 34:2587-92. [PMID: 23843041 DOI: 10.1093/carcin/bgt246] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Sulforaphane (SFN) is a potent inducer of detoxication enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase (GST) via the Kelch-like erythroid-derived protein with CNC homology-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signaling pathway. NQO1 reduces the carcinogenic estrogen metabolite, catechol estrogen-3,4-quinone, whereas GSTs detoxify it through conjugation with glutathione. These 3,4-quinones can react with DNA to form depurinating DNA adducts. Thus, SFN may alter estrogen metabolism and thus protect against estrogen-mediated DNA damage and carcinogenesis. Human breast epithelial MCF-10A cells were treated with either vehicle or SFN and either estradiol (E2) or its metabolite 4-hydroxyestradiol (4-OHE2). 4-Hydroxy-derived estrogen metabolites and depurinating DNA adducts formed from E2 and its interconvertable metabolite estrone (E1) were analyzed by mass spectrometry. Levels of the depurinated adducts, 4-OHE1/2-1-N3Adenine and 4-OHE1/2-1-N7Guanine, were reduced by 60% in SFN-treated cells, whereas levels of 4-OCH3E1/2 and 4-OHE1/2-glutathione conjugates increased. To constitutively enhance the expression of Nrf2-regulated genes, cells were treated with either scrambled or siKEAP1 RNA. Following E2 or 4-OHE2 treatments, levels of the adenine and guanine adducts dropped 60-70% in siKEAP1-treated cells, whereas 4-OHE1/2-glutathione conjugates increased. However, 4-OCH3E1/2 decreased 50% after siKEAP1 treatment. Thus, treatment with SFN or siKEAP1 has similar effects on reduction of depurinating estrogen-DNA adduct levels following estrogen challenge. However, these pharmacologic and genetic approaches have different effects on estrogen metabolism to O-methyl and glutathione conjugates. Activation of the Nrf2 pathway, especially elevated NQO1, may account for some but not all of the protective effects of SFN against estrogen-mediated DNA damage.
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Affiliation(s)
- Li Yang
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Mosli HA, Tolba MF, Al-Abd AM, Abdel-Naim AB. Catechol estrogens induce proliferation and malignant transformation in prostate epithelial cells. Toxicol Lett 2013; 220:247-58. [DOI: 10.1016/j.toxlet.2013.05.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 05/03/2013] [Accepted: 05/06/2013] [Indexed: 10/26/2022]
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Gaikwad NW. Metabolomic profiling unravels DNA adducts in human breast that are formed from peroxidase mediated activation of estrogens to quinone methides. PLoS One 2013; 8:e65826. [PMID: 23762435 PMCID: PMC3675060 DOI: 10.1371/journal.pone.0065826] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 04/30/2013] [Indexed: 12/18/2022] Open
Abstract
Currently there are three major hypotheses that have been proposed for estrogen induced carcinogenicity, however exact etiology remains unknown. Based on the chemical logic, studies were undertaken to investigate if estrogens could generate quinone methides in an oxidative environment which then could cause DNA damage in humans. In presence of MnO2 estrogens were oxidized to quinone methides. Surprisingly quinone methides were found to be stable with t1/2 of 20.8 and 4.5 min respectively. Incubation of estrogens with lactoperoxidase (LPO) and H2O2 resulted in formation of respective quinone methides (E1(E2)-QM). Subsequent addition of adenine to the assay mixture lead to trapping of E1(E2)-QM, resulting in formation of adenine adducts of estrogens, E1(E2)-9-N-Ade. Targeted ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) based metabolomic analysis of the breast tissue extracts showed the presence of adenine adducts of estrogens, E1(E2)-9-N-Ade, along with other estrogen related metabolites. Identity of E1(E2)-N-Ade in LPO assay extracts and breast tissue extracts were confirmed by comparing them to pure synthesized E1(E2)-9-N-Ade standards. From these results, it is evident that peroxidase enzymes or peroxidase-like activity in human breast tissue could oxidize estrogens to electrophilic and stable quinone methides in a single step that covalently bind to DNA to form adducts. The error prone repair of the damaged DNA can result in mutation of critical genes and subsequently cancer. This article reports evidence for hitherto unknown estrogen metabolic pathway in human breast, catalyzed by peroxidase, which could initiate cancer.
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Affiliation(s)
- Nilesh W. Gaikwad
- Department of Nutrition and Department of Environmental Toxicology, University of California Davis, Davis, California, United States of America
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Chen ST, Chen DR, Fang JP, Lin PH. 2,3,7,8-Tetrachlorodibenzo-p-dioxin modulates estradiol-induced aldehydic DNA lesions in human breast cancer cells through alteration of CYP1A1 and CYP1B1 expression. Breast Cancer 2013; 22:269-79. [DOI: 10.1007/s12282-013-0476-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 04/29/2013] [Indexed: 10/26/2022]
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