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Saroj S, Kana Veedu A, Reddy U C, Venkatesan N, Verma AK, Kannoth Manheri M. Modulation of Doxorubicin-Induced ROS Accumulation in Cardiomyocytes Using Ibuprofen-Conjugated Synthetic Lipids as Carriers. ACS APPLIED BIO MATERIALS 2025. [PMID: 40408375 DOI: 10.1021/acsabm.4c01932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2025]
Abstract
Conjugation of an NSAID such as ibuprofen to the head group of oxanorbornane-based lipids and the use of their aggregates as carriers for doxorubicin (Dox) are discussed here. These conjugates were characterized by various spectroscopic techniques, including 2D-NMR, and insights into their assembly were gathered through PXRD, AFM, SEM, DLS, and qNano techniques. Free lipids as well as their formulations (lipid:cholesterol:Dox in a 3:1.5:2 molar ratio) showed a high tendency to form solid lipid particles, which was verified by TEM analysis. The presence of the ibuprofen unit led to an increase in interlipid spacing and a characteristic change in their packing. Active loading through a pH gradient allowed us to achieve high drug entrapment and a controlled release profile. The formulation AT3.3, prepared by this method, showed a Dox entrapment of ∼90%, with a controlled release of ∼18% by the end of 24 h; only ∼66% of the entrapped Dox was released by the end of 5 days. Cytotoxicity studies in NIH3T3 cells and hemolytic assay results showed that these lipids and their formulations have a good safety profile. Results from flow cytometry experiments in A549 cells revealed that the formulation AT3.3 induces effects similar to free Dox, with cell cycle arrest predominantly at the S phase and G2/M phase. At the same time, the response from the blank formulation was comparable to that of the control. Confocal microscopy studies in NIH3T3 and A549 cells showed that free Dox gets localized mainly in the nucleus, while the use of the carrier (AT3.3) causes significant localization of the drug on the cytoplasmic side as well. ROS induction due to free Dox and its formulation (AT3.3) in cardiomyocytes and A549 cells was also compared, and the results showed a protective effect in cardiomyocytes when using this formulation.
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Affiliation(s)
- Soumya Saroj
- Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India
| | - Akshaya Kana Veedu
- Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India
| | - Chandrasekhar Reddy U
- Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India
| | - Nalini Venkatesan
- Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600 036, India
| | - Abhishek K Verma
- Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India
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Palma M. Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges. Vaccines (Basel) 2025; 13:344. [PMID: 40333213 PMCID: PMC12030785 DOI: 10.3390/vaccines13040344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 05/09/2025] Open
Abstract
Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body's immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody-drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines-including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines-aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes.
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Affiliation(s)
- Marco Palma
- Institute for Globally Distributed Open Research and Education (IGDORE), 03181 Torrevieja, Spain
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Singh MT, Thaggikuppe Krishnamurthy P, Magham SV. Harnessing the synergistic potential of NK1R antagonists and selective COX-2 inhibitors for simultaneous targeting of TNBC cells and cancer stem cells. J Drug Target 2024; 32:258-269. [PMID: 38252517 DOI: 10.1080/1061186x.2024.2309568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/11/2024] [Indexed: 01/24/2024]
Abstract
Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.
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Affiliation(s)
- Madhu Tanya Singh
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Praveen Thaggikuppe Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Sai Varshini Magham
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
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Wu M, Zhang W, Zhou X, Wang Z, Li S, Guo C, Yang Y, Zhang R, Zhang Z, Sun X, Gong T. An in situ forming gel co-loaded with pirarubicin and celecoxib inhibits postoperative recurrence and metastasis of breast cancer. Int J Pharm 2024; 653:123897. [PMID: 38360289 DOI: 10.1016/j.ijpharm.2024.123897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/16/2024] [Accepted: 02/07/2024] [Indexed: 02/17/2024]
Abstract
Surgical removal combined with postoperative chemotherapy is still the mainstay of treatment for most solid tumors. Although chemotherapy reduces the risk of recurrence and metastasis after surgery, it may produce serious adverse effects and impair patient compliance. In situ drug delivery systems are promising tools for postoperative cancer treatment, improving drug delivery efficiency and reducing side effects. Herein, an injectable phospholipid-based in situ forming gel (IPG) was prepared for the co-delivery of antitumor agent pirarubicin (THP) and cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) in the surgical incision, and the latter are used extensively in adjuvant chemotherapy for cancer. After injection, the IPG co-loaded with THP and CXB (THP-CXB-IPG) underwent spontaneous phase transition and formed a drug reservoir that fitted the irregular surgical incisions perfectly. In vitro drug release studies and in vivo pharmacokinetic analysis had demonstrated the sustained release behaviors of THP-CXB-IPG. The in vivo therapeutic efficacy was evaluated in mice that had undergone surgical resection of breast cancer, and the THP-CXB-IPG showed considerable inhibition of residual tumor growth after surgery and reduced the incidence of pulmonary metastasis. Moreover, it reduced the systemic toxicity of chemotherapeutic agents. Therefore, THP-CXB-IPG can be a promising candidate for preventing postoperative recurrence and metastasis.
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Affiliation(s)
- Mengying Wu
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Wei Zhang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xueru Zhou
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zijun Wang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Sha Li
- NMPA Key Laboratory for Technical Research on Drug Products in Vitro and in Vivo Correlation, Bioanalytical Service Center of Sichuan Institute for Drug Control, Chengdu 611731, China
| | - Chenqi Guo
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yuping Yang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Rongping Zhang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xun Sun
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Tao Gong
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
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Shams A, Alzahrani AA, Ayash TA, Tamur S, AL-Mourgi M. The Multifaceted Roles of Myrrha in the Treatment of Breast Cancer: Potential Therapeutic Targets and Promises. Integr Cancer Ther 2024; 23:15347354241309659. [PMID: 39707884 PMCID: PMC11663268 DOI: 10.1177/15347354241309659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/07/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Breast cancer is a critical threat to human health, and effective targeted agents showing lower systemic toxicity are still lacking. Therefore, exploring new potent therapeutic candidates with a broader safety margin is warranted. Alternative medicine, which has historically been used in traditional Chinese medicine, has played an increasingly prominent role in this area of research. This study introduces Commiphora myrrha (or myrrh) as a potential therapeutic candidate for treating breast cancer patients. Myrrh bioactive extracts have been used traditionally for decades to treat numerous medical disorders, including cancers, specifically breast cancer. Nonetheless, myrrh's precise rudimentary mechanisms of action in regulating genes involved in breast cancer evolution and progression remain elusive. PURPOSE Herein, we use a network pharmacology platform to identify the potential genes targeted by myrrh-active molecules in breast cancer. METHOD The identified targets' expression profiles were determined at the mRNA and protein levels using The Breast Cancer Gene-Expression Miner v5.0 (bcGen-ExMiner v5.0) and The Human Protein Atlas datasets, respectively. A gene signature composed of the specifically designated genes was constructed, and its association with different breast cancer molecular subtypes was investigated through the Gene expression-based Outcome for Breast Cancer (GOBO) online tool. The protein mapping relationship between potential myrrh targets and their partner proteins during breast cancer development was screened and constructed through the STRING and ShinyGO databases. In addition, the Kaplan-Meier plots (KM-plot) prognostic tool was applied to assess the survival rate associated with the expression of the current gene signature in different human cancers, including breast cancer. RESULTS Combining the results of network pharmacology with other bioinformatics databases suggests that myrrh's active components exert anti-cancer effects by regulating genes involved in breast cancer pathogenesis, particularly PTGS2, EGFR, ESR2, MMP2, and JUN. An individual evaluation of the expression profiles of these genes at both mRNA and protein levels reveals that a high expression profile of each gene is associated with breast cancer advancement. Moreover, the GOBO analysis shows an elevated expression profile of the PTGS2/ESR2/EGFR/JUN/MMP2 genes' signature in the most aggressive breast cancer subtype (Basal) in breast tumor samples and breast cancer cell lines. Furthermore, the STRING protein interaction network and the KEGG analyses indicate that myrrh exerts therapeutic effects on breast cancer by regulating several biological processes such as cell proliferation, cell migration, apoptosis, and various signaling pathways, including TNF, PI3K-Akt, NF-κB, and MAPK. Consistently, breast cancer patients with high expression of this genes' signature display poor survival outcomes. CONCLUSIONS The present study is the first attempt to explore the biological involvement of myrrh-targeted genes during breast cancer development. Therefore, suppressing the effects of the intended genes' signature using myrrh extracts would provide encouraging results in blocking breast cancer tumorigenesis. Thus, our findings provide conclusive evidence and deepen the current understanding of the molecular role of myrrh in the treatment of breast cancer, further supporting its clinical application.
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Affiliation(s)
- Anwar Shams
- Department of Pharmacology, College of Medicine, Taif University, Taif, Saudi Arabia
- Research Center for Health Sciences, Deanship of Graduate Studies and Scientific Research, Taif University, Taif, Saudi Arabia
- High Altitude Research Center, Taif University, Taif, Saudi Arabia
| | | | - Taghreed A Ayash
- Department of General Science, Ibnsina International Medical College, Jeddah, Saudi Arabia
- Research and Innovation Central lab, Chair of Research and Innovation Central Lab, Ibnsina International Medical College, Jeddah, Saudi Arabia
| | - Shadi Tamur
- Department of Pediatric, College of Medicine, Taif University, Taif, Saudi Arabia
| | - Majed AL-Mourgi
- Department of Surgery, College of Medicine, Taif University, Taif, Saudi Arabia
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Alqinyah M, Alhamed AS, Alnefaie HO, Algahtani MM, Badr AM, Albogami AM, Mohany M, Alassmrry YA, Alghaith AF, Alhamami HN, Alhazzani K, Alanazi AZ, Alsaidan OA. Targeting Store-Operated Calcium Entry Regulates the Inflammation-Induced Proliferation and Migration of Breast Cancer Cells. Biomedicines 2023; 11:1637. [PMID: 37371732 PMCID: PMC10296208 DOI: 10.3390/biomedicines11061637] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/24/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Persistent challenges complicating the treatment of breast cancer remain, despite some recent undeniable successes. Sufficient evidence currently exists demonstrating the crucial role of inflammation, characterized by the enhanced activation of Toll-like receptor 4 (TLR4) and the COX-2/PGE2 pathway, in the migration and proliferation of breast cancer cells. Interestingly, the store-operated calcium entry (SOCE) pathway was shown to be essential for the TLR4 activity and COX-2 expression in immune cells such as macrophages and microglia. However, whether SOCE influences inflammatory signaling and the inflammation-induced proliferation and migration of breast cancer cells is still unknown. Thus, the current study intended to delineate the role of SOCE in the TLR4-induced inflammation, migration, and proliferation of breast cancer cells. To this end, MDA-MB-231 breast cancer cells were treated with lipopolysaccharide (LPS) to activate TLR4, BTP2 to inhibit SOCE, and Thapsigargin to induce SOCE. Following these treatments, several experiments were conducted to evaluate the proliferation and migration rates of the MDA-MB-231 cells and the expression of several inflammatory and oncogenic genes, including COX-2, PGE2, IL-6, IL-8, and VEGF. Different techniques were used to achieve the aims of this study, including qRT-PCR, Western blotting, ELISA, MTT, and wound healing assays. This study shows that SOCE inhibition using BTP2 suppressed the LPS-induced migration and proliferation of breast cancer cells. Additionally, treatment with LPS caused approximately six- and three-fold increases in COX-2 mRNA and protein expression, respectively, compared to the controls. The LPS-induced elevations in the COX-2 mRNA and protein levels were suppressed by BTP2 to the control levels. In addition to its effect on COX-2, BTP2 also suppressed the LPS-induced productions of PGE2, IL-6, IL-8, and VEGF. Conversely, SOCE induction using Thapsigargin enhanced the LPS-induced inflammation, migration, and proliferation of breast cancer cells. Collectively, these results provide evidence for the potentially important role of SOCE in inflammation-induced breast cancer progression processes. Thus, we argue that the current study may provide novel targets for designing new therapeutic approaches for the treatment of breast cancer.
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Affiliation(s)
- Mohammed Alqinyah
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abdullah S. Alhamed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Hajar O. Alnefaie
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad M. Algahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Amira M. Badr
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abdullah M. Albogami
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohamed Mohany
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Yasseen A. Alassmrry
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Adel F. Alghaith
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Hussain N. Alhamami
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Khalid Alhazzani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Z. Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Omar Awad Alsaidan
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia
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Hazlett J, Niemi V, Aiderus A, Powell K, Wise L, Kemp R, Dunbier AK. Oestrogen deprivation induces chemokine production and immune cell recruitment in in vitro and in vivo models of oestrogen receptor-positive breast cancer. Breast Cancer Res 2021; 23:95. [PMID: 34602068 PMCID: PMC8489094 DOI: 10.1186/s13058-021-01472-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 09/20/2021] [Indexed: 12/09/2022] Open
Abstract
Background Oestrogen receptor-positive (ER+) breast cancer is commonly treated using endocrine therapies such as aromatase inhibitors which block synthesis of oestradiol, but the influence of this therapy on the immune composition of breast tumours has not been fully explored. Previous findings suggest that tumour infiltrating lymphocytes and immune-related gene expression may be altered by treatment with aromatase inhibitors. However, whether these changes are a direct result of impacts on the host immune system or mediated through tumour cells is not known. We aimed to investigate the effect of oestrogen deprivation on the expression of chemokines and immune infiltration in vitro and in an ER+ immunocompetent mouse model. Methods RT-qPCR and a bead-based Bioplex system were used to investigate the expression of chemokines in MCF-7 breast cancer cells deprived of oestrogen. A migration assay and flow cytometry were used to measure the migration of human peripheral blood mononuclear cells (PBMCs) to MCF-7 cells grown without the main biologically active oestrogen, oestradiol. Using flow cytometry and immunohistochemistry, we examined the immune cell infiltrate into tumours created by injecting SSM3 ER+ breast cancer cells into wild-type, immunocompetent 129/SvEv mice. Results This study demonstrates that oestrogen deprivation increases breast cancer secretion of TNF, CCL5, IL-6, IL-8, and CCL22 and alters total human peripheral blood mononuclear cell migration in an in vitro assay. Oestrogen deprivation of breast cancer cells increases migration of CD4+ T cells and decreases migration of CD11c+ and CD14+ PBMC towards cancer cells. PBMC migration towards breast cancer cells can be reduced by treatment with the non-steroidal anti-inflammatory drugs, aspirin and celecoxib. Treatment with endocrine therapy using the aromatase inhibitor letrozole increases CD4+ T cell infiltration into ER+ breast cancer tumours in immune competent mice. Conclusions These results suggest that anti-oestrogen treatment of ER+ breast cancer cells can alter cytokine production and immune cells in the area surrounding the cancer cells. These findings may have implications for the combination and timing of anti-oestrogen therapies with other therapies. Supplementary Information The online version contains supplementary material available at 10.1186/s13058-021-01472-1.
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Affiliation(s)
- Jody Hazlett
- Department of Biochemistry, University of Otago, Dunedin, New Zealand.
| | - Virginia Niemi
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Aziz Aiderus
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Katelyn Powell
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Lyn Wise
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Roslyn Kemp
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Anita K Dunbier
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
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Combinatorial targeting of microRNA-26b and microRNA-101 exerts a synergistic inhibition on cyclooxygenase-2 in brain metastatic triple-negative breast cancer cells. Breast Cancer Res Treat 2021; 187:695-713. [PMID: 34041621 DOI: 10.1007/s10549-021-06255-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/04/2021] [Indexed: 12/16/2022]
Abstract
PURPOSE Extravasation of triple-negative (TN) metastatic breast cancer (BC) cells through the brain endothelium (BE) is a critical step in brain metastasis (BM). During extravasation, metastatic cells induce alteration in the inter-endothelial junctions and transmigrate through the endothelial barrier. Transmigration of metastatic cells is mediated by the upregulation of cyclooxygenase-2 (COX-2) that induces matrix metalloproteinase-1 (MMP-1) capable of degrading inter-endothelial junctional proteins. Despite their important role in BM, the molecular mechanisms upregulating COX-2 and MMP-1 in TNBC cells remain poorly understood. In this study, we unraveled a synergistic effect of a pair of micro-RNAs (miR-26b-5p and miR-101-3p) on COX-2 expression and the brain transmigration ability of BC cells. METHODS Using a gain-and-loss of function approach, we modulated levels of miR-26b-5p and miR-101-3p in two TNBC cell lines (the parental MDA-MB-231 and its brain metastatic variant MDA-MB-231-BrM2), and examined the resultant effect on COX-2/MMP-1 expression and the transmigration of cancer cells through the BE. RESULTS We observed that the dual inhibition of miR-26b-5p and miR-101-3p in BC cells results in higher increase of COX-2/MMP-1 expression and a higher trans-endothelial migration compared to either micro-RNA alone. The dual restoration of both micro-RNAs exerted a synergistic inhibition on COX-2/MMP-1 by targeting COX-2 and potentiated the suppression of trans-endothelial migration compared to single micro-RNA. CONCLUSION These findings provide new insights on a synergism between miR-26-5p and miR-101-3p in regulating COX-2 in metastatic TNBC cells and shed light on miR-26-5p and miR-101-3p as prognostic and therapeutic targets that can be exploited to predict or prevent BM.
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Sadeghi S, Tapak M, Ghazanfari T, Mosaffa N. A review of Sulfur Mustard-induced pulmonary immunopathology: An Alveolar Macrophage Approach. Toxicol Lett 2020; 333:115-129. [PMID: 32758513 DOI: 10.1016/j.toxlet.2020.07.035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 12/27/2022]
Abstract
Despite many studies investigating the mechanism of Sulfur Mustard (SM) induced lung injury, the underlying mechanism is still unclear. Inflammatory and subsequent fibroproliferative stages of SM-toxicity are based upon several highly-related series of events controlled by the immune system. The inhalation of SM gas variably affects different cell populations within the lungs. Various studies have shown the critical role of macrophages in triggering a pulmonary inflammatory response as well as its maintenance, resolution, and repair. Importantly, macrophages can serve as either pro-inflammatory or anti-inflammatory populations depending on the present conditions at any pathological stage. Different characteristics of macrophages, including their differentiation, phenotypic, and functional properties, as well as interactions with other cell populations determine the outcomes of lung diseases and the extent of long- or short-term pulmonary damage induced by SM. In this paper, we summarize the current state of knowledge regarding the role of alveolar macrophages and their mediators in the pathogenesis of SM in pulmonary injury. Investigating the specific cells and mechanisms involved in SM-lung injury may be useful in finding new target opportunities for treatment of this injury.
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Affiliation(s)
- Somaye Sadeghi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahtab Tapak
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tooba Ghazanfari
- Immunoregulation Research Center, Shahed University, Tehran, Iran; Department of Immunology, Shahed University, Tehran, Iran.
| | - Nariman Mosaffa
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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de Souza CP, Alves B, Waisberg J, Fonseca F, Carmo ADO, Gehrke F. Detection of COX-2 in liquid biopsy in patients with breast cancer. J Clin Pathol 2020; 73:826-829. [DOI: 10.1136/jclinpath-2020-206576] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 11/04/2022]
Abstract
AimsTo determine the expression of the cyclooxygenase-2 (COX-2) gene in patients with breast cancer attended at the Centro Universitário Saúde ABC/Faculdade de Medicina do ABC (CUS-ABC/FMABC) outpatient clinic. Breast cancer is the most common cancer in women worldwide. More than two million new cases are reported annually. An overexpression of COX-2 has been observed in many cancers. COX-2 is related to parameters of cancer aggressiveness, including tumour size, positive nodal state and lower survival, and to angiogenesis and resistance to apoptosis.Methods15 mL of peripheral blood was obtained from 34 patients and 21 healthy women. The extracellular RNA of QIAamp RNA was submitted to an RNA sequestration kit for RNA reverse transcriptase. Quantitative real-time PCR was performed using COX-2-specific oligonucleotides and the endogenous Glyceraldehyde-3-Phosphate Dehydrogenase gene.ResultsThe mean remission time was 53 years. The mean progression time was 33 months. The difference observed between the patient and control groups in median COX-2 expression (p<0.001) was significant.ConclusionsPatients with breast cancer showed a higher mean COX-2 expression in peripheral blood samples at diagnosis than the control group. Since this information could prove important in the diagnosis and prognosis of breast cancer, further research is required on larger patient samples.
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11
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Cai Y, Yousef A, Grandis JR, Johnson DE. NSAID therapy for PIK3CA-Altered colorectal, breast, and head and neck cancer. Adv Biol Regul 2020; 75:100653. [PMID: 31594701 PMCID: PMC7056575 DOI: 10.1016/j.jbior.2019.100653] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/12/2019] [Accepted: 09/13/2019] [Indexed: 12/21/2022]
Abstract
Epidemiologic evidence indicates that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) provides a protective effect against the development of colorectal, breast, and head and neck cancers. Genomic characterization of these cancers has lent considerable insight into the subpopulations of cancer patients who are most likely to benefit from NSAID therapy. The PIK3CA gene encodes the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) and is among the most frequently mutated genes in solid tumor malignancies. Cancer-associated mutations in PIK3CA promote signaling via the PI3K pathway and stimulate tumor cell growth. In addition, activation of the PI3K pathway leads to induction of cyclooxygenase-2 (COX-2) enzyme and production of immunosuppressive prostaglandin E2 (PGE2). Notably, in both colorectal cancer and head and neck cancer the subpopulation of patients that benefit from NSAID use is restricted to those whose tumors exhibit PIK3CA genomic alterations. Preclinical studies, particularly in models of head and neck cancer, support the hypothesis that the chemopreventive impact of NSAIDs may be due, in part, to inhibition of COX-2 and reduction of PGE2 levels in the tumor microenvironment.
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Affiliation(s)
- Yi Cai
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Andrew Yousef
- School of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Jennifer R Grandis
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Daniel E Johnson
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA.
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12
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Curry JM, Besmer DM, Erick TK, Steuerwald N, Das Roy L, Grover P, Rao S, Nath S, Ferrier JW, Reid RW, Mukherjee P. Indomethacin enhances anti-tumor efficacy of a MUC1 peptide vaccine against breast cancer in MUC1 transgenic mice. PLoS One 2019; 14:e0224309. [PMID: 31693710 PMCID: PMC6834267 DOI: 10.1371/journal.pone.0224309] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 10/10/2019] [Indexed: 01/27/2023] Open
Abstract
In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing.
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Affiliation(s)
- Jennifer M. Curry
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Dahlia M. Besmer
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Timothy K. Erick
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Nury Steuerwald
- Molecular Biology and Genomics Laboratory, Carolinas Medical Center, Charlotte, NC, United States of America
| | - Lopamudra Das Roy
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Priyanka Grover
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Shanti Rao
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Sritama Nath
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Jacob W. Ferrier
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Robert W. Reid
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, United States of America
| | - Pinku Mukherjee
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America
- OncoTAb, Inc., Charlotte, NC, United States of America
- * E-mail:
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13
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Elias A, Shebaby WN, Nehme B, Faour W, Bassil BS, Hakim JE, Iskandar R, Dib-Jalbout N, Mroueh M, Daher C, Taleb RI. In Vitro and In Vivo Evaluation of the Anticancer and Anti-inflammatory Activities of 2-Himachelen-7-ol isolated from Cedrus Libani. Sci Rep 2019; 9:12855. [PMID: 31492934 PMCID: PMC6731217 DOI: 10.1038/s41598-019-49374-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 08/23/2019] [Indexed: 11/20/2022] Open
Abstract
Cedrus libani is a majestic evergreen tree native to the Mediterranean mountains of Lebanon, Syria and Turkey. In this study, the tree heart wood was extracted using hexane to produce C. libani oil extract (CLOE) as a dark oil. GCMS analysis of CLOE identified up to 30 compounds whereby 2-himachalen-7-ol (7-HC) was the most abundant (40%). 7-HC was isolated using column chromatography and the identity of the white crystalline solid was confirmed via NMR spectroscopy and X-Ray Crystallography. 7-HC demonstrated potent cytotoxic activity against several human cancer cell lines including brain (SF-268, IC50 8.1 μg/mL) and colon (HT-29, IC50 10.1 μg/mL; Caco-2, IC50 9.9 μg/mL) with ovarian (Sk-OV-3, IC50 > 50 μg/mL) cells being the most resistant. However, while HT-29 displayed resistance to Cisplatin, 7-HC was 8–10 folds more potent. Co-treatment with 7-HC and Cisplatin showed a significant synergistic anti-proliferative effect against SF-268, HT-29 and Caco-2 cells. 7-HC also exhibited significant anti-inflammatory effect in formalin-induced paw edema in rats. Western blot analysis revealed that 7-HC displayed dose dependent inhibition of LPS-induced COX-2 protein expression in isolated rat monocytes. The present study demonstrates that 7-HC possesses promising anticancer and anti-inflammatory activities, and may serve as a lead molecule in cancer therapy.
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Affiliation(s)
- Andree Elias
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Wassim N Shebaby
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Bilal Nehme
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Wissam Faour
- School of Medicine, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Bassem S Bassil
- Faculty of Arts and Sciences, University of Balamand, PO Box 100, Tripoli, Lebanon
| | - Joelle El Hakim
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Rita Iskandar
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Nahia Dib-Jalbout
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Mohamad Mroueh
- School of Pharmacy, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Costantine Daher
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon
| | - Robin I Taleb
- Department of Natural Sciences, Lebanese American University, Byblos, 1102 2801, Lebanon.
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Beigi Harchegani A, Tahmasbpour E, Borna H, Imamy A, Ghanei M, Shahriary A. Free Radical Production and Oxidative Stress in Lung Tissue of Patients Exposed to Sulfur Mustard: An Overview of Cellular and Molecular Mechanisms. Chem Res Toxicol 2018; 31:211-222. [PMID: 29569912 DOI: 10.1021/acs.chemrestox.7b00315] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Sulfur mustard (SM) is a chemical alkylating compound that primary targets lung tissue. It causes a wide variety of pathological effects in respiratory system such as chronic bronchitis, bronchiolitis obliterans, necrosis of the mucosa and inflammation, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. However, molecular and cellular mechanisms for these pathologies are still unclear. Oxidative stress (OS) induced by reactive oxygen species (ROS) is likely a significant mechanism by which SM leads to cell death and tissues injury. SM can trigger various molecular and cellular pathways that are linked to ROS generation, OS, and inflammation. Hypoxia-induced oxidative stress, reduced activity of enzymatic antioxidants, depletion of intercellular glutathione (GSH), decreased productivity of GSH-dependent antioxidants, mitochondrial dysfunction, accumulation of leukocytes and proinflammatory cytokines, and increased expression of ROS producing-related enzymes and inflammatory mediators are the major events in which SM leads to massive production of ROS and OS in pulmonary system. Therefore, understanding of these molecules and signaling pathways gives us valuable information about toxicological effects of SM on injured tissues and the way for developing a suitable clinical treatment. In this review, we aim to discuss the possible mechanisms by which SM induces excessive production of ROS, OS, and antioxidants depletion in lung tissue of exposed patients.
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Affiliation(s)
- Asghar Beigi Harchegani
- Chemical Injuries Research Center , System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences , 19945-581 Tehran , Iran
| | - Eisa Tahmasbpour
- Laboratory of Regenerative Medicine & Biomedical Innovations , Pasteur Institute of Iran , Tehran , Iran
| | - Hojat Borna
- Chemical Injuries Research Center , System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences , 19945-581 Tehran , Iran
| | - Ali Imamy
- Chemical Injuries Research Center , System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences , 19945-581 Tehran , Iran
| | - Mostafa Ghanei
- Chemical Injuries Research Center , System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences , 19945-581 Tehran , Iran
| | - Alireza Shahriary
- Chemical Injuries Research Center , System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences , 19945-581 Tehran , Iran
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15
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Tahmasbpour E, Ghanei M, Khor A, Panahi Y. Altered expression of cyclooxygenase-2, 12-lipoxygenase, inducible nitric oxide synthase-2 and surfactant protein D in lungs of patients with pulmonary injury caused by sulfur mustard. Drug Chem Toxicol 2018. [PMID: 29536762 DOI: 10.1080/01480545.2018.1442474] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
CONTEXT Sulfur mustard (SM) is a strong alkylating toxicant that targets different organs, particularly human lung tissue. Change in genes expression is one of the molecular mechanisms of SM toxicity in damaged tissue. OBJECTIVE The purpose of this investigation is to characterize the expression of cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LO), inducible nitric oxide synthase 2 (iNOS2), and surfactant protein D (SFTPD) in lungs of patients who exposed to SM. METHODS Lung biopsies were provided from SM-exposed patients (n = 6) and controls (n = 5). Total RNA were extracted from all specimens and then cDNA was synthesized for each sample. Changes in gene expression were measured using RT2 Profiler ™PCR Array. RESULTS Pulmonary function tests revealed more obstructive and restrictive spirometric patterns among patients compared to the control group. Expression of COX-2 and 12-LO in the lung of patients was increased by 6.2555 (p = 0.004) and 6.2379-folds (p = 0.002), respectively. In contrast, expression of SF-D and iNOS genes was reduced by 8.5869-fold (p = 0.005) and 2.4466-folds (p = 0.011), respectively. CONCLUSIONS Mustard lungs were associated with overexpression of COX-2 and 12-LO, which are responsible for inflammation, overproduction of free radicals and oxidative stress. Downregulation of iNOS2 and SF-D are probably the reason for lung disease and dysfunction among these patients. Therefore, the expression of these genes could be an important, routine part of the management of such patients.
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Affiliation(s)
- Eisa Tahmasbpour
- a Chemical Injuries Research Center , Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Mostafa Ghanei
- a Chemical Injuries Research Center , Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Abolfazl Khor
- a Chemical Injuries Research Center , Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Yunes Panahi
- a Chemical Injuries Research Center , Baqiyatallah University of Medical Sciences , Tehran , Iran
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16
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Kochel TJ, Reader JC, Ma X, Kundu N, Fulton AM. Multiple drug resistance-associated protein (MRP4) exports prostaglandin E2 (PGE2) and contributes to metastasis in basal/triple negative breast cancer. Oncotarget 2018; 8:6540-6554. [PMID: 28029661 PMCID: PMC5351651 DOI: 10.18632/oncotarget.14145] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 11/22/2016] [Indexed: 02/02/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) and its primary enzymatic product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. In order to elucidate the factors contributing to intratumoral PGE2 levels, we evaluated the expression of COX-2/PGE2 pathway members MRP4, the prostaglandin transporter PGT, 15-PGDH (PGE2 metabolism), the prostaglandin E receptor EP4, COX-1, and COX-2 in normal, luminal, and basal breast cancer cell lines. The pattern of protein expression varied by cell line reflecting breast cancer heterogeneity. Overall, basal cell lines expressed higher COX-2, higher MRP4, lower PGT, and lower 15-PGDH than luminal cell lines resulting in higher PGE2 in the extracellular environment. Genetic or pharmacologic suppression of MRP4 expression or activity in basal cell lines led to less extracellular PGE2. The key finding is that xenografts derived from a basal breast cancer cell line with stably suppressed MRP4 expression showed a marked decrease in spontaneous metastasis compared to cells with unaltered MRP4 expression. Growth properties of primary tumors were not altered by MRP4 manipulation. In addition to the well-established role of high COX-2 in promoting metastasis, these data identify an additional mechanism to achieve high PGE2 in the tumor microenvironment; high MRP4, low PGT, and low 15-PGDH. MRP4 should be examined further as a potential therapeutic target in basal breast cancer.
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Affiliation(s)
- Tyler J Kochel
- University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Jocelyn C Reader
- University of Maryland School of Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Baltimore, MD, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Xinrong Ma
- University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Namita Kundu
- University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Amy M Fulton
- University of Maryland School of Medicine, Department of Pathology, Baltimore, MD, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.,Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA
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17
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Harris RE, Casto BC, Harris ZM. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol 2014; 5:677-692. [PMID: 25302170 PMCID: PMC4129532 DOI: 10.5306/wjco.v5.i4.677] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 02/28/2014] [Accepted: 03/14/2014] [Indexed: 02/06/2023] Open
Abstract
Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2 (COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following: (1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis; (2) essential features of mammary carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2 (PGE-2) biosynthesis; (3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis; (4) extrahepatic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and (5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of COX-2 and the prostaglandin cascade in the “inflammogenesis of breast cancer”.
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18
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Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer. Indian J Surg Oncol 2014; 5:59-65. [PMID: 24669166 DOI: 10.1007/s13193-014-0290-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 01/20/2014] [Indexed: 10/25/2022] Open
Abstract
COX-2 regulates tumour growth, invasion and metastasis in breast cancer. This study investigated the association between COX-2 expression in human breast cancer versus the expression of ER, PR, HER-2/neu, as well as its association with other established prognostic indicators like age, menopausal status, tumour size, lymph nodal status, stage, grade, NPI and histological subtype, and aims to validate the role of overexpression of COX-2 as a prognostic marker in patients with breast cancer in Indian subcontinent. In this hospital based study of 123 breast cancer patients (Group-A) and 76 female patients with benign breast disease (Group-B) attending a Comprehensive Breast Clinic at a reputed institute in Eastern India, COX-2 protein expression was measured from breast tissue using the Western Blot Technique. COX-2 mRNA expression was measured by RT-PCR Technique. ER, PR and HER-2/neu status was measured by immunohistochemistry methods. COX-2 was not expressed in the control group. The proportion of COX-2 positive tumours was significantly higher in patients of age >50 years [52(91.2 %), p < 0.01], postmenopausal status [64(90.1 %), p < 0.01], advanced stage of disease (p < 0.01), higher grade (p < 0.01), larger tumors (p < 0.01), metastatic lymph nodes (p < 0.01) and NPI ≥ 5.4 (p < 0.01). COX-2 expression was seen in ER-negative [66(95.7 %), p < 0.01], PR-negative [76(92.7 %), p < 0.01], and HER-2/neu positive tumours [29(100.0 %), p < 0.01]. Risk of COX-2 positivity was found to be 2.74 times more for postmenopausal status, 6.90 times more for large size tumours (≥ 2.5), 34.37 times more for node positive tumours, 9.26 times more with ER negative patients and 5.88 times more for PR negative patients. COX-2 expression is associated with established indicators of poor prognosis such as postmenopausal status, age >50 year, advanced stage of disease, large tumour size, higher grade, lymph node metastasis, NPI ≥ 5.4, ER negativity, PR negativity and HER-2/neu positivity. Thus, COX-2 expression implies aggressive tumour biology, and may play an important role as a prognostic marker.
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Abstract
Ductal carcinoma in situ (DCIS) is responsible for 25% of screen-detected breast cancers. Various prognostic classifications are in use, including the Van Nuys Prognostic Index and the European Organisation for Research and Treatment of Cancer grading system (well, intermediate or poorly differentiated) based on cytonuclear pattern. This has been modified in screening programs to low, intermediate and high grade. In comparison with normal epithelium, DCIS has a tenfold increase in growth and 15-fold increase in apoptosis. Patients with extensive or multifocal DCIS need mastectomy and sentinel node biopsy, together with reconstruction, if requested. Microinvasion associated with DCIS is an indication for sentinel node biopsy. Randomized trials have confirmed the value of breast irradiation after wide excision, in terms of DCIS relapse and progression to invasive disease. Patients with estrogen receptor-positive DCIS benefit from adjuvant tamoxifen after breast-conserving surgery.
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Affiliation(s)
- Tracey Irvine
- Guy's Hospital, Hedley Atkins Breast Unit, London, UK
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20
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Inflammatory and microenvironmental factors involved in breast cancer progression. Arch Pharm Res 2013; 36:1419-31. [PMID: 24222504 DOI: 10.1007/s12272-013-0271-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 10/21/2013] [Indexed: 12/20/2022]
Abstract
The primary reason for the high mortality rate of breast cancer is metastasis, which can result in a poor survival rate. The tumor environment is important for promotion and invasion of cancer cells. Recent studies have shown that inflammation is associated with breast cancer. Therefore, it is important to investigate the role of the inflammatory and microenvironment in breast cancer progression and metastasis. The present review summarizes some of the markers for inflammation and breast cancer invasion, which may aid in the design of an appropriate therapy for metastatic breast cancer. The following four inflammatory markers are discussed in this review: (1) Tumor associated macrophages (TAMs); (2) Matrix metalloproteinases (MMPs); (3) Sphingosine 1-phosphate (S1P); (4) C-reactive protein (CRP). TAMs are commonly found in breast cancer patients, and high infiltration is positively correlated with poor prognosis and low survival rate. MMPs are well-known for their roles in the degradation of ECM components when cancer cells invade and migrate. MMPs are also associated with inflammation through recruitment of a variety of stromal cells such as fibroblasts and leukocytes. S1P is an inflammatory lipid and is involved in various cellular processes such as proliferation, survival, and migration. Recent studies indicate that S1P participates in breast cancer invasion in various ways. CRP is used clinically to indicate the outcome of cancer patients as well as acute inflammatory status. This review summarizes the current understanding on the role of S1P in CRP expression which promotes the breast epithelial cell invasion, suggesting a specific mechanism linking inflammation and breast cancer. The present review might be useful for understanding the relationship between inflammation and breast cancer for the development of pharmacological interventions that may control the primary molecules involved in the breast cancer microenvironment.
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21
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Thorat D, Sahu A, Behera R, Lohite K, Deshmukh S, Mane A, Karnik S, Doke S, Kundu GC. Association of osteopontin and cyclooxygenase-2 expression with breast cancer subtypes and their use as potential biomarkers. Oncol Lett 2013; 6:1559-1564. [PMID: 24260046 PMCID: PMC3834357 DOI: 10.3892/ol.2013.1600] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 07/31/2013] [Indexed: 12/18/2022] Open
Abstract
Breast cancer is one of the most common malignant tumors among females worldwide and remains a leading cause of cancer-related mortality. Due to the heterogeneous clinical nature of breast cancer, it is necessary to identify new biomarkers that are associated with tumor growth, angiogenesis and metastasis. Osteopontin (OPN) and cyclooxygenase-2 (COX-2) are known to be overexpressed in invasive breast cancer and their overexpression is associated with aggressive histological and clinical features. The present study assessed OPN and COX-2 expression in various subtypes of breast cancer. The expression of OPN and COX-2 was analyzed using immunohistochemistry (IHC) in a cohort of 67 invasive ductal breast carcinoma patients. The statistical analysis was performed using standard statistical software SPSS version 18.0. The associations between OPN and COX-2 and the human epidermal growth factor receptor type 2 (HER2)-overexpressing and non-HER2-overexpressing subtypes were evaluated using the Mann-Whitney U test. The mean OPN level was significantly higher in the HER2-overexpressing subtype compared with the non-HER2-overexpressing subtype. Furthermore, the mean COX-2 expression levels were higher in the HER2-overexpressing subtype compared with the luminal A, luminal B or triple-negative groups. It is well known that carcinomas overexpressing HER2/neu have a worse prognosis than luminal tumors. Hence, it may be hypothesized that an elevated expression of OPN and COX-2 in a HER2-overexpressing subtype may contribute to a more aggressive behavior and be used as diagnostic and prognostic markers in breast cancer.
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Affiliation(s)
- Dhanashri Thorat
- Department of Tumor Biology, Angiogenesis and Nanomedicine, National Centre for Cell Science, Pune, Maharashtra 411007, India
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22
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Martinson HA, Lyons TR, Giles ED, Borges VF, Schedin P. Developmental windows of breast cancer risk provide opportunities for targeted chemoprevention. Exp Cell Res 2013; 319:1671-8. [PMID: 23664839 PMCID: PMC3980135 DOI: 10.1016/j.yexcr.2013.04.018] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 04/26/2013] [Accepted: 04/28/2013] [Indexed: 12/12/2022]
Abstract
The magnitude of the breast cancer problem implores researchers to aggressively investigate prevention strategies. However, several barriers currently reduce the feasibility of breast cancer prevention. These barriers include the inability to accurately predict future breast cancer diagnosis at the individual level, the need for improved understanding of when to implement interventions, uncertainty with respect to optimal duration of treatment, and negative side effects associated with currently approved chemoprevention therapies. None-the-less, the unique biology of the mammary gland, with its postnatal development and conditional terminal differentiation, may permit the resolution of many of these barriers. Specifically, lifecycle-specific windows of breast cancer risk have been identified that may be amenable to risk-reducing strategies. Here, we argue for prevention research focused on two of these lifecycle windows of risk: postpartum mammary gland involution and peri-menopause. We provide evidence that these windows are highly amenable to targeted, limited duration treatments. Such approaches could result in the prevention of postpartum and postmenopausal breast cancers, correspondingly.
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Affiliation(s)
- Holly A Martinson
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC1S, 8401K, 12801 East 17th Avenue, Aurora, CO 80045, USA; Program in Cancer Biology, University of Colorado Anschutz Medical Campus, MS8104, RC1S, 5117, 12801 East 17th Avenue, Aurora, CO 80045, USA
| | - Traci R Lyons
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC1S, 8401K, 12801 East 17th Avenue, Aurora, CO 80045, USA
| | - Erin D Giles
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus School of Medicine, RC1S, Room 7103, 12801 East 17th Avenue, Mail Stop 8106, Aurora, CO 80045, USA; Anschutz Health and Wellness Center, 12348 East Montview Boulevard, Campus Box C263, Aurora, CO 80045, USA
| | - Virginia F Borges
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC1S, 8401K, 12801 East 17th Avenue, Aurora, CO 80045, USA; University of Colorado Cancer Center, Building 500, Suite 6004C, 13001 East 17th Place, Aurora, CO 80045, USA; Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO 80045, USA
| | - Pepper Schedin
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, MS8117, RC1S, 8401K, 12801 East 17th Avenue, Aurora, CO 80045, USA; Program in Cancer Biology, University of Colorado Anschutz Medical Campus, MS8104, RC1S, 5117, 12801 East 17th Avenue, Aurora, CO 80045, USA; University of Colorado Cancer Center, Building 500, Suite 6004C, 13001 East 17th Place, Aurora, CO 80045, USA; Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO 80045, USA.
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Howe LR. Pharmacologic Interventions with NSAIDs. OBESITY, INFLAMMATION AND CANCER 2013:257-303. [DOI: 10.1007/978-1-4614-6819-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Immunohistochemical expression of cyclooxygenase-2 in patients with advanced cancer of the larynx who have undergone induction chemotherapy with the intention of preserving phonation. Clin Transl Oncol 2012; 14:682-8. [PMID: 22855152 DOI: 10.1007/s12094-012-0859-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Accepted: 12/06/2011] [Indexed: 10/28/2022]
Abstract
INTRODUCTION Cyclooxygenase-2 (COX2) is an enzyme that plays a role in different stages of the carcinogenic process and has prognostic and predictive values that have not yet been established. The objective of this study was to evaluate the role of COX2 overexpression in advanced squamous cell carcinoma of the larynx that has been treated with a phonation conservation protocol. MATERIALS AND METHODS This study included a retrospective analysis of 59 patients with resectable tumours that were treated with chemotherapy (CT) and/or radiation therapy (RT). The expression levels of COX2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor (VEGFR-2) in collected biopsy specimens were determined via immunohistochemistry. RESULTS Forty-four percent of the included samples demonstrated overexpression of COX2. In the statistical analysis, COX2 overexpression did not correlate with other clinical or treatment efficacy prognostic factors; however, the median global survival (OS) of patients whose tumours expressed COX2 was 79 months, whereas COX2-negative patients had a median OS of only 38 months, although this finding did not reach statistical significance. The other analysed biological parameters did not demonstrate a significant relationship with COX2. CONCLUSIONS COX2 overexpression was a common finding in our study. The results obtained did not reveal relationships with established prognostic categories; however, the difference in survival between patients with and without COX2 expression justifies the need for future prospective studies that utilise a larger patient sample size.
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Taromaru GCM, DE Oliveira VM, Silva MALG, Montor WR, Bagnoli F, Rinaldi JF, Aoki T. Interaction between cyclooxygenase-2 and insulin-like growth factor in breast cancer: A new field for prevention and treatment. Oncol Lett 2011; 3:682-688. [PMID: 22740976 DOI: 10.3892/ol.2011.532] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 12/12/2011] [Indexed: 01/24/2023] Open
Abstract
The objective of this study was to evaluate the correlation between cyclooxygenase-2 (COX-2) and markers of cell proliferation and apoptosis, including, Bcl-2, Bax, Ki-67 and the type I insulin-like growth factor (IGF) receptor (IGF1-R) in ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC), present in the same surgical specimen. A total of 110 cases were evaluated using tissue microarrays. Cases were classified in scores from 0 to 3 according to pre-defined methods. The results showed that the positivity rates were COX-2 in 87% of cases in DCIS and IDC; Bcl-2 in 55% of cases in DCIS and IDC; Bax in 23% of cases in IDC and 19% in DCIS, IGF-1 in 24% of cases in DCIS and IDC; and Ki-67 in 81% of cases in DCIS and IDC. We also observed a positive correlation between the expression of COX-2 and IGF1-R (p=0.045). Our results demonstrate a positive correlation between the expression of COX-2 and IGF1-R in DCIS and IDC, demonstrating that they are involved in breast cancer carcinogenesis. Further studies are required to prove the effectiveness of COX-2 and IGF1-R inhibitors for the prevention and treatment of breast cancer, as well as to explain their mechanism of action.
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Affiliation(s)
- Giuliana Cássia Morrone Taromaru
- Department of Obstetrics and Gynecology, Irmandade da Santa Casa de Misericórdia de São Paulo and Santa Casa de São Paulo, Faculty of Medical Sciences, São Paulo, Brazil
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26
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Chuah BYS, Putti T, Salto-Tellez M, Charlton A, Iau P, Buhari SA, Wong CI, Tan SH, Wong ALA, Chan CW, Goh BC, Lee SC. Serial changes in the expression of breast cancer-related proteins in response to neoadjuvant chemotherapy. Ann Oncol 2011; 22:1748-54. [PMID: 21355070 DOI: 10.1093/annonc/mdq755] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Tumour expression of cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), erythroblastic leukaemia viral oncogene homologue-2 (ErbB2), Ki-67 and p53 in breast cancer are associated with poorer outcomes. We investigated in vivo changes of these proteins with neoadjuvant chemotherapy. PATIENTS AND METHODS Four core biopsies were taken from 100 breast cancer patients at baseline, during and upon completion of neoadjuvant chemotherapy. Immunohistochemical expression of these proteins were evaluated and correlated with clinicopathological features, clinical response and progression-free survival (PFS). RESULTS There was a statistically significant change from positivity to negativity in COX-2 expression with chemotherapy (P = 0.002), predominantly in clinical responders (P = 0.002). COX-2-positive tumours that remained positive had shorter PFS than those that turned negative. Estrogen receptor (ER)+ and COX-2+ tumours at baseline that remained COX-2+ fared worse than those that became COX-2 negative (PFS 27 versus 52 months, P = 0.002). No significant changes in IHC expression were observed for ER, progesterone receptor, ErbB2, EGFR, p53 or Ki67. CONCLUSIONS Chemotherapy induced change in COX-2 expression from positivity to negativity predominantly among clinical responders and is associated with longer PFS. Interaction between COX-2 and ER was observed, suggesting that some hormone receptor-positive patients may benefit from combining COX-2 inhibition with hormonal therapy.
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Affiliation(s)
- B Y S Chuah
- Department of Haematology-Oncology, National University Health System, Singapore
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Miglietta A, Toselli M, Ravarino N, Vencia W, Chiecchio A, Bozzo F, Motta M, Torchio B, Bocca C. COX-2 expression in human breast carcinomas: correlation with clinicopathological features and prognostic molecular markers. Expert Opin Ther Targets 2010; 14:655-64. [DOI: 10.1517/14728222.2010.486792] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Abraham JE, Harrington P, Driver KE, Tyrer J, Easton DF, Dunning AM, Pharoah PDP. Common polymorphisms in the prostaglandin pathway genes and their association with breast cancer susceptibility and survival. Clin Cancer Res 2009; 15:2181-91. [PMID: 19276290 DOI: 10.1158/1078-0432.ccr-08-0716] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE There is evidence that genetic variation in the prostaglandin pathway affects cancer susceptibility and progression. Conflicting data from several studies exist for the association of PTGS2 (cyclooxygenase 2) polymorphisms with breast cancer risk. We investigated associations between common germ-line variations in seven genes in the prostaglandin pathway and breast cancer susceptibility and survival among women with invasive breast cancer in the SEARCH study. EXPERIMENTAL DESIGN DNA samples from 9,030 cases and controls were genotyped for 64 single nucleotide polymorphisms tagging known common variants (minor allele frequency > 0.05) in PTGS1, PTGS2, TBXAS1, PTGIS, PTGES, PTGDS, and PGDS with a two-stage case-control study design. RESULTS Four tagging single nucleotide polymorphisms showed modest association with breast cancer susceptibility. All four fit a recessive genetic model. Minor allele homozygotes for PTGISrs5602 [odds ratio (OR), 1.15; 95% confidence interval (95% CI), 1.04-1.27; P = 0.005], PTGISrs8183919 (OR, 1.22; 95% CI, 1.06-1.41; P = 0.006), and TBXASrs41727 (OR, 1.83; 95% CI, 1.22-2.73; P = 0.003) are associated with an increased risk compared with common allele carriers. For PTGISrs44627 minor allele homozygotes (OR, 0.66; 95% CI, 0.5-0.86; P = 0.002), a protective effect was observed. CONCLUSION Specific PTGIS and TBXAS1 variants may affect breast cancer susceptibility, but common variants in PTGS1, PTGS2, PTGES, PTGDS, and PGDS have no major role in breast cancer susceptibility. None of the variants in the seven genes studied appear to affect survival. Further larger studies correlating clinical and genotypic data are required to establish if the clinical utility of prostaglandin-targeted therapies, as chemoprevention agents, is influenced by an individual's profile of genetic variants in key prostaglandin pathway genes.
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Affiliation(s)
- Jean E Abraham
- Cancer Research UK Department of Oncology, University of Cambridge, United Kingdom.
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29
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Visscher DW, Pankratz VS, Santisteban M, Reynolds C, Ristimäki A, Vierkant RA, Lingle WL, Frost MH, Hartmann LC. Association between cyclooxygenase-2 expression in atypical hyperplasia and risk of breast cancer. J Natl Cancer Inst 2008; 100:421-7. [PMID: 18334709 DOI: 10.1093/jnci/djn036] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The cyclooxygenase-2 (COX-2) enzyme, which is induced by inflammatory and mitogenic stimuli, plays a protumorigenic role in several human cancers. COX-2 is overexpressed in invasive and in situ breast cancers. Atypical hyperplasia in breast tissue, although benign, is associated with a high risk of breast cancer. We investigated whether COX-2 overexpression in atypical hyperplasia is associated with the risk of subsequent breast cancer. METHODS COX-2 expression was assessed immunohistochemically in archival sections from 235 women with atypia whose biopsy specimens were obtained at the Mayo Clinic from January 1, 1967, through December 31, 1991. COX-2 expression was scored as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong). Risk factor information and follow-up for breast cancer events were obtained via a study questionnaire and the medical records. All statistical tests were two-sided. RESULTS Forty-one (17%) of the 235 women developed breast cancer during a median follow-up of 15 years. Moderate (category 2+) or strong (category 3+) COX-2 expression was identified in 71 (30%) and 34 (14%) of the 235 samples, respectively. The risk for developing breast cancer, relative to a control population (the Iowa Surveillance, Epidemiology, and End Results registry), increased with increasing COX-2 expression (relative risk [RR] = 2.63, 95% confidence interval [CI] = 1.56 to 4.15, for those with negative or weak COX-2 expression; RR = 3.56, 95% CI = 1.94 to 5.97, for those with moderate expression; and RR = 5.66, 95% CI = 2.59 to 10.75, for those with strong expression; P = .07). Overexpression of COX-2 was statistically significantly associated with the type of atypia (lobular vs ductal, P < .001), number of foci of atypia in the biopsy (P = .02), and older age at time of biopsy (>45 years, P = .01). CONCLUSIONS COX-2 appears to be a biomarker that further stratifies breast cancer risk among women with atypia and may be a relevant target for chemoprevention strategies.
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Affiliation(s)
- Daniel W Visscher
- Department of Surgical Pathology, University of Michigan, Ann Arbor, MI, USA
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Abstract
Many human cancers exhibit elevated prostaglandin (PG) levels due to upregulation of cyclooxygenase-2 (COX-2), a key enzyme in eicosanoid biosynthesis. COX-2 over-expression has been observed in about 40% of cases of invasive breast carcinoma and at a higher frequency in preinvasive ductal carcinoma in situ tumors, Extensive pharmacologic and genetic evidence implicates COX enzymes in neoplasia. Epidemiologic analyses demonstrate a protective effect of COX-inhibiting nonsteroidal anti-inflammatory drugs with respect to human cancer. Complementary experimental studies have established that both conventional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors suppress mammary tumor formation in rodent breast cancer models. Furthermore, knocking out Cox-2 reduces mammary tumorigenesis and angiogenesis, and, conversely, transgenic COX-2 over-expression induces tumor formation. The utility of COX/PG signaling as a target for chemoprevention has been established by randomized controlled clinical trials. However, these studies also identified increased cardiovascular risk associated with use of selective COX-2 inhibitors. Thus, current efforts are directed toward identifying safer approaches to antagonizing COX/PG signaling for cancer prevention and treatment, with a particular focus on PGE2 regulation and signaling, because PGE2 is a key protumorigenic prostanoid.
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Affiliation(s)
- Louise R Howe
- Department of Cell & Developmental Biology, Weill Medical College of Cornell University, York Avenue, New York, New York 10021, USA.
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Dursun P, Yuce K, Usubutun A, Ayhan A. Cyclooxygenase-2 expression in cervical intraepithelial neoplasia III and squamous cell cervical carcinoma, and its correlation with clinicopathologic variables. Int J Gynecol Cancer 2007; 17:164-73. [PMID: 17291249 DOI: 10.1111/j.1525-1438.2007.00798.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The objective of the study was to compare cyclooxygenase-2 (COX-2) expression in cervical intraepithelial neoplasia III (CIN III) and squamous cell carcinoma (SCC) of the cervix, and its correlation with clinicopathologic factors of SCC with a review of the available literature. This study included 25 patients with CIN III and 67 patients with stage I-IIa SCC. All patients in the SCC group were treated with radical hysterectomy plus pelvic and para-aortic lymphadenectomy and postoperative chemoradiotherapy based on their histopathologic risk factors. Immunohistochemical analysis was performed on paraffin-embedded sections with COX-2 antibody. COX-2 expression in the SCC group was significantly higher than in the CIN III group (55.2% [37/67] vs 24% [6/25]; P= 0.008). Significantly higher expression of COX-2 was observed in patients with lymphovascular space invasion (LVSI) compared to patients without LVSI (61.9% [34/55] vs 33.3% [3/9]; P= 0.02). Additionally, patients with tumor sizes >4 cm had significantly higher COX-2 expression than patients with tumor sizes <4 cm (65.9% [27/41] vs 39% [10/26] P= 0.028). There was no significant relationship with respect to COX-2 expression and parametrial involvement, lymph node metastasis, recurrences, and survival. In multivariate analysis, LVSI was the only statistically significant determinant for COX-2 expression (P= 0.024; OR = 2.35; 95% CI = 1.1-4.9). Our results and a review of the literature both suggest that COX-2 expression may have a role in the development and progression of CIN III and it is related to some clinicopathologic variables of cervical carcinoma. Further studies are needed to clarify the role of COX-2 inhibitors in the management of CIN and SCC.
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Affiliation(s)
- P Dursun
- Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
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32
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Oliveira VM, Piato S, Silva MALG. Correlation of cyclooxygenase-2 and aromatase immunohistochemical expression in invasive ductal carcinoma, ductal carcinoma in situ, and adjacent normal epithelium. Breast Cancer Res Treat 2006; 95:235-41. [PMID: 16322898 DOI: 10.1007/s10549-005-9010-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The purpose of our study was to evaluate the correlation between cyclooxygenase-2 (COX-2) and aromatase immunohistochemical expression in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) present in the same breast, as well as in adjacent stroma and normal epithelium, we still correlated with nuclear grade, histologic grade, presence or absence of comedonecrosis, tumor size, and age at diagnosis. Forty-seven cases were evaluated through the use of anti-aromatase and anti-COX-2 polyclonal antibodies. Making the correlation of COX-2 and aromatase expression, we observed that COX-2 expression in IDC was correlated with aromatase expression in IDC (p < 0.001), DCIS (p < 0.001), normal epithelium (p = 0.024), and stroma tumor (p < 0.001). When the correlation was made between COX-2 expression in DCIS with aromatase, we observed positive correlation in IDC (p < 0.001), DCIS (p < 0.001), normal epithelium (p = 0.013), and stroma tumor (p < 0.001). In the correlative analysis of COX-2 expression in normal epithelium with aromatase in different evaluated tissues, we observed the following statistical results: IDC (p < 0.001), DCIS (p < 0.001), normal epithelium (p = 0.005), and stroma tumor (p = 0.047). Our results demonstrate the high correlation between COX-2 and aromatase expression in IDC, DCIS and normal epithelium, showing the importance of these two enzymes in the induction, promotion and progression of breast cancer.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Aromatase/metabolism
- Biomarkers, Tumor
- Breast/pathology
- Breast Neoplasms/enzymology
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/enzymology
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Intraductal, Noninfiltrating/enzymology
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Cyclooxygenase 2/metabolism
- Epithelium/enzymology
- Epithelium/pathology
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Immunoenzyme Techniques
- Membrane Proteins/metabolism
- Middle Aged
- Neoplasm Invasiveness/pathology
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Canney PA, Machin MA, Curto J. A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor Celecoxib in post-menopausal patients with advanced breast cancer. Eur J Cancer 2006; 42:2751-6. [PMID: 17027257 DOI: 10.1016/j.ejca.2006.08.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2006] [Accepted: 08/16/2006] [Indexed: 11/22/2022]
Abstract
BACKGROUND This was a feasibility study of the combination of Exemestane and the cyclooxygenase-2 (COX-2) inhibitor Celecoxib in advanced breast cancer. PATIENTS AND METHODS Post-menopausal women with histologically proven, hormone receptor positive, advanced breast cancer who had progressive disease, normal blood counts, liver and renal function were eligible. Exemestane was given at a dose of 25 mg daily and Celecoxib at a dose of 400 mg bd. Responses were assessed according to RECIST criteria and toxicity was accessed according to CTC. The primary end-point was the percentage of patients who had neither discontinued therapy nor progressed at 6 months ('treatment successes'). RESULTS Fifty-three eligible patients were enrolled. Of 30 patients with target lesions, 4 (13%) had a complete response (CR), 12 (40%) a partial response (PR) and 5 (17%) stable disease (SD). The best response in 18 of the 23 patients with no target lesions at baseline was stable disease. The clinical benefit (CR, PR+SD) for the whole group was therefore 39/53 (74%). The 'treatment success' rate was 60%. There were two non-malignant deaths which may have been associated with treatment. CONCLUSION The combination of Exemestane and Celecoxib shows promising activity and tolerability and these results support the use of this combination in phase III clinical trials of short duration treatments.
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Affiliation(s)
- P A Canney
- Beatson Oncology Centre, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK.
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Mehrotra S, Morimiya A, Agarwal B, Konger R, Badve S. Microsomal prostaglandin E2 synthase-1 in breast cancer: a potential target for therapy. J Pathol 2006; 208:356-63. [PMID: 16353170 DOI: 10.1002/path.1907] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The anti-tumour actions of cyclooxygenases (COX) are thought to be mediated by inhibition of prostaglandin E(2) (PGE(2)) synthesis. However, COX-2 inhibition also alters cellular production of other prostaglandins such as prostacyclin (PGI(2)). The latter action is believed to be important for the development of adverse cardio-vascular events. Microsomal PGES (mPGES-1) is an enzyme downstream to COX-2 and affects PGE(2) production only. It is possible that targeting mPGES-1 could decrease PGE(2) production without affecting PGI(2) production. In order to assess the potential of mPGES-1 as a target for therapy, we analysed its expression in breast cell lines and normal and malignant breast tissues. The expression of mPGES-1 and COX-2 was correlated in tumour cells and vascular endothelium, and with prognostic parameters in breast cancer. Although not detectable in normal epithelial cells, expression was noted in areas of fibrocystic change and in situ carcinoma. mPGES-1 expression was noted in 79% of breast cancer tissues. Its expression did not correlate with COX-2 overexpression or with prognostic markers of breast cancer. Endothelial cells did not show mPGES-1 expression. Upregulation of mPGES-1 is therefore frequent in pre-malignant and malignant breast disease. In this study, coordinate over-expression of COX-2 and mPGES-1 was not observed, particularly in the endothelial cells of blood vessels. Targeting mPGES-1 might prove to be an alternative therapeutic strategy to inhibit PGE2 production.
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Affiliation(s)
- Sanjana Mehrotra
- Department of Pathology, Indiana University, Indianapolis, Indiana 46202, USA
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Nakopoulou L, Mylona E, Papadaki I, Kapranou A, Giannopoulou I, Markaki S, Keramopoulos A. Overexpression of cyclooxygenase-2 is associated with a favorable prognostic phenotype in breast carcinoma. Pathobiology 2006; 72:241-9. [PMID: 16374068 DOI: 10.1159/000089418] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2004] [Accepted: 07/05/2005] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. The purpose of the present study was to investigate the involvement of COX-2 protein in breast cancer biological behavior through its correlation with the well-known clinicopathological parameters and the expression of p53, c-erbB-2, topoisomerase IIalpha (topoIIalpha) and peroxisome proliferator-activated receptor (PPARgamma) proteins, as well as its effect on patients' survival. METHODS We performed immunohistochemistry to detect COX-2, estrogen receptor (ER), progesterone receptor (PR), p53, c-erbB-2, topoIIalpha and PPARgamma proteins in 175 cases of invasive breast carcinomas. The results were elaborated by statistic analysis. RESULTS Cytoplasmic expression of COX-2 was detected in 66.9% of breast carcinoma samples and was inversely correlated with both nuclear and histological grade (p < 0.0001 and p = 0.039, respectively), whereas its association with PR was found to be positive (p = 0.016). COX-2 expression was inversely correlated with topoIIalpha and p53 (p = 0.033 and p = 0.002, respectively), whereas its association with PPARgamma was parallel (p < 0.0001). In addition, c-erbB-2 of tumor cells was inversely correlated with COX-2 in stromal cells of the tumor (p = 0.011). Neither univariate nor multivariate analysis demonstrated any association between COX-2 expression and patient overall or disease-free survival. CONCLUSIONS The current data suggest that increased expression of COX-2 may be related to breast carcinomas with less aggressive phenotype. This suggestion is further supported by the positive correlation between COX-2 and PPARgamma, since the latter is considered to be indicative of a less malignant phenotype of tumor cells.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/enzymology
- Breast Neoplasms/pathology
- Breast Neoplasms/surgery
- Carcinoma, Ductal, Breast/enzymology
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/surgery
- Carcinoma, Lobular/enzymology
- Carcinoma, Lobular/pathology
- Cyclooxygenase 2/metabolism
- Disease-Free Survival
- Female
- Humans
- Immunoenzyme Techniques
- Middle Aged
- PPAR gamma/metabolism
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Affiliation(s)
- L Nakopoulou
- Department of Pathology, Medical School of Athens University, Athens, Greece.
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