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Nishide G, Ishibashi T, Lim K, Qiu Y, Hazawa M, Matsushima A, Wong RW. Zooming into Gene Activation: Estrogen Receptor α Dimerization and DNA Binding Visualized by High-Speed Atomic Force Microscopy. ACS NANO 2025; 19:15395-15410. [PMID: 40249907 PMCID: PMC12045019 DOI: 10.1021/acsnano.4c14943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/20/2025]
Abstract
Estrogen receptor α (ERα) is pivotal in gene regulation, particularly in estrogen-responsive cancers. However, the full-length molecular dynamic structure of ERα remains elusive. In this study, we employ high-speed atomic force microscopy (HS-AFM) to visualize ERα interactions with the estrogen response element (ERE) under both ligand-present and ligand-absent conditions. ERα binds to ERE even in the absence of estrogen, although the presence of the ligand significantly enhances binding precision and stability. Our real-time, high-resolution HS-AFM imaging captures ERα structural transitions from monomeric to dimeric forms, elucidating the molecular mechanisms by which estrogen modulates DNA-binding specificity. Based on these findings, we propose a ligand-induced dimerization (LID) model, wherein estrogen facilitates the optimal loading of ERα onto DNA. These insights deepen our understanding of hormone signaling in cancer and hold promise for the development of future therapeutic strategies targeting hormone-related malignancies.
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Affiliation(s)
- Goro Nishide
- Division
of Nano Life Science in the Graduate School of Frontier Science Initiative,
WISE Program for Nano-Precision Medicine, Science and Technology, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Tomoka Ishibashi
- Laboratory
of Structure−Function Biochemistry, Department of Chemistry,
Faculty of Science, Kyushu University, Fukuoka 819-0395, Japan
| | - Keesiang Lim
- WPI
Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa 920-1192, Japan
| | - Yujia Qiu
- Division
of Nano Life Science, Graduate School of Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan
| | - Masaharu Hazawa
- WPI
Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa 920-1192, Japan
- Cell-Bionomics
Research Unit, Innovative Integrated Bio-Research Core, Institute
for Frontier Science Initiative, Kanazawa
University, Kanazawa 920-1192, Japan
| | - Ayami Matsushima
- Laboratory
of Structure−Function Biochemistry, Department of Chemistry,
Faculty of Science, Kyushu University, Fukuoka 819-0395, Japan
| | - Richard W. Wong
- WPI
Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa 920-1192, Japan
- Cell-Bionomics
Research Unit, Innovative Integrated Bio-Research Core, Institute
for Frontier Science Initiative, Kanazawa
University, Kanazawa 920-1192, Japan
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2
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Islam F, Javdan SB, Lewis MR, Craig JD, Wu H, Deans TL. Programming megakaryocytes to produce engineered platelets for delivering non-native proteins. Commun Biol 2025; 8:638. [PMID: 40253534 PMCID: PMC12009418 DOI: 10.1038/s42003-025-08017-8] [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: 11/09/2023] [Accepted: 03/28/2025] [Indexed: 04/21/2025] Open
Abstract
Platelets are anucleate cells naturally filled with secretory granules that store large amounts of protein to be released in response to certain physiological conditions. Cell engineering can endow platelets with the ability to deliver non-native proteins by modifying them as they develop during the cell fate process. This study presents a strategy to efficiently generate mouse platelets from pluripotent stem cells and demonstrates their potential as bioengineered protein delivery platforms. By modifying megakaryocytes, the progenitor cells of platelets, we successfully engineered platelets capable of packaging and delivering non-native proteins. These engineered platelets can offer flexible delivery platforms to release non-native proteins in a controlled manner upon activation when packaged into α-granules or deliver active enzymes to genetically alter recipient cells. Our findings highlight platelets as a promising tool for protein delivery in cell therapy applications.
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Affiliation(s)
- Farhana Islam
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
| | - Shwan B Javdan
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
| | - Mitchell R Lewis
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
| | - James D Craig
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
| | - Han Wu
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Tara L Deans
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
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3
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Tran TH, Le TH, Nguyen THT, Vong LB, Nguyen MTT, Nguyen NT, Dang PH. Discovery of Alkyl Triphenylphosphonium Pinostrobin Derivatives as Potent Anti-Breast Cancer Agents. Chem Biodivers 2024; 21:e202400864. [PMID: 38699953 DOI: 10.1002/cbdv.202400864] [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: 04/03/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/05/2024]
Abstract
Pinostrobin demonstrated anticancer properties, but its hydrophobic feature led to a reduction in bioavailability. The mitochondria-targeted approach successfully synthesized eight new alkyl triphenylphosphonium pinostrobin derivatives (1-8) with good yield in this study. Seven compounds (1-3, 5-8) showed greater cytotoxic potency against the human MCF-7 breast cancer cell line than pinostrobin. Molecular docking studies were performed with two important targets in hormone-dependent anticancer strategies, estrogen receptor α (ERα) ligand binding domains, 3ERT (antagonist recognition and antiproliferative function), and 1GWR (agonist recognition and pro-proliferative function). In addition, the MD simulation study of the two most potent compounds (2 and 3) complexed with both ERα forms suggested that compounds 2 and 3 could serve as favourable antagonists. Furthermore, the in silico ADMET prediction indicated that compounds 2 and 3 could be potential drug candidates.
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Affiliation(s)
- Tu Hoai Tran
- Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
- Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
- Research Lab for Drug Discovery and Development, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
| | - Tho Huu Le
- Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
- Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
- Research Lab for Drug Discovery and Development, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
| | - Thu-Ha Thi Nguyen
- School of Biomedical Engineering, International University, Quarter 6, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
- Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
| | - Long Binh Vong
- School of Biomedical Engineering, International University, Quarter 6, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
- Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
| | - Mai Thanh Thi Nguyen
- Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
- Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
- Research Lab for Drug Discovery and Development, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
| | - Nhan Trung Nguyen
- Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
- Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
- Research Lab for Drug Discovery and Development, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
| | - Phu Hoang Dang
- Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
- Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc City, Ho Chi Minh City, 71300, Vietnam
- Research Lab for Drug Discovery and Development, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, 72711, Vietnam
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Neagu AN, Bruno P, Johnson KR, Ballestas G, Darie CC. Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era. Int J Mol Sci 2024; 25:4113. [PMID: 38612922 PMCID: PMC11012526 DOI: 10.3390/ijms25074113] [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: 03/03/2024] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/14/2024] Open
Abstract
Precision oncology is based on deep knowledge of the molecular profile of tumors, allowing for more accurate and personalized therapy for specific groups of patients who are different in disease susceptibility as well as treatment response. Thus, onco-breastomics is able to discover novel biomarkers that have been found to have racial and ethnic differences, among other types of disparities such as chronological or biological age-, sex/gender- or environmental-related ones. Usually, evidence suggests that breast cancer (BC) disparities are due to ethnicity, aging rate, socioeconomic position, environmental or chemical exposures, psycho-social stressors, comorbidities, Western lifestyle, poverty and rurality, or organizational and health care system factors or access. The aim of this review was to deepen the understanding of BC-related disparities, mainly from a biomedical perspective, which includes genomic-based differences, disparities in breast tumor biology and developmental biology, differences in breast tumors' immune and metabolic landscapes, ecological factors involved in these disparities as well as microbiomics- and metagenomics-based disparities in BC. We can conclude that onco-breastomics, in principle, based on genomics, proteomics, epigenomics, hormonomics, metabolomics and exposomics data, is able to characterize the multiple biological processes and molecular pathways involved in BC disparities, clarifying the differences in incidence, mortality and treatment response for different groups of BC patients.
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Affiliation(s)
- Anca-Narcisa Neagu
- Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I bvd. 20A, 700505 Iasi, Romania
| | - Pathea Bruno
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.B.); (K.R.J.); (G.B.)
| | - Kaya R. Johnson
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.B.); (K.R.J.); (G.B.)
| | - Gabriella Ballestas
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.B.); (K.R.J.); (G.B.)
| | - Costel C. Darie
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.B.); (K.R.J.); (G.B.)
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Ge Y, Ni X, Li J, Ye M, Jin X. Roles of estrogen receptor α in endometrial carcinoma (Review). Oncol Lett 2023; 26:530. [PMID: 38020303 PMCID: PMC10644365 DOI: 10.3892/ol.2023.14117] [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: 08/10/2023] [Accepted: 10/06/2023] [Indexed: 12/01/2023] Open
Abstract
Endometrial carcinoma (EC) is a group of endometrial epithelial malignancies, most of which are adenocarcinomas and occur in perimenopausal and postmenopausal women. It is one of the most common carcinomas of the female reproductive system. It has been shown that the occurrence and development of EC is closely associated with the interaction between estrogen (estradiol, E2) and estrogen receptors (ERs), particularly ERα. As a key nuclear transcription factor, ERα is a carcinogenic factor in EC. Its interactions with upstream and downstream effectors and co-regulators have important implications for the proliferation, metastasis, invasion and inhibition of apoptosis of EC. In the present review, the structure of ERα and the regulation of ERα in multiple dimensions are described. In addition, the classical E2/ERα signaling pathway and the crosstalk between ERα and other EC regulators are elucidated, as well as the therapeutic targeting of ERα, which may provide a new direction for clinical applications of ERα in the future.
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Affiliation(s)
- Yidong Ge
- Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
- Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Xiaoqi Ni
- Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
- Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Jingyun Li
- Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
- Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Meng Ye
- Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
- Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Xiaofeng Jin
- Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang 315020, P.R. China
- Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
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6
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Zhang X, Huang L, Sun J, Liu J, Zong Y, Wan L, Yang X, Yan X, Zhang Y, Zhao R, Liu J, Zhong H, Wei C, Yang X, Tai Y, Han Y, Wang Y. Monopolar spindle 1 contributes to tamoxifen resistance in breast cancer through phosphorylation of estrogen receptor α. Breast Cancer Res Treat 2023; 202:595-606. [PMID: 37695401 DOI: 10.1007/s10549-023-07098-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 08/06/2023] [Indexed: 09/12/2023]
Abstract
PURPOSE The overexpression of mitotic kinase monopolar spindle 1 (Mps1) has been identified in many tumor types, and targeting Mps1 for tumor therapy has shown great promise in multiple preclinical cancer models. However, the role played by Mps1 in tamoxifen (TAM) resistance in breast cancer has never been reported. METHODS The sensitivity of breast cancer cells to tamoxifen was analysed in colony formation assays and wound healing assays. Enhanced transactivational activity of estrogen receptor α (ERα) led by Mps1 overexpression was determined by luciferase assays. The interaction between Mps1 and ERα was verified by co-immunoprecipitation and proximity ligation assay. Phosphorylation of ERα by Mps1 was detected by in vitro kinase assay and such phosphorylation process in vivo was proven by co-immunoprecipitation. The potential phosphorylation site(s) of ERα were analyzed by mass spectrometry. RESULTS Mps1 determines the sensitivity of breast cancer cells to tamoxifen treatment. Mps1 overexpression rendered breast cancer cells more resistant to tamoxifen, while an Mps1 inhibitor or siMps1 oligos enabled cancer cells to overcome tamoxifen resistance. Mechanistically, Mps1 interacted with estrogen receptor α and stimulated its transactivational activity in a kinase activity-dependent manner. Mps1 was critical for ERα phosphorylation at Thr224 amino acid site. Importantly, Mps1 failed to enhance the transactivational activity of the ERα-T224A mutant. CONCLUSION Mps1 contributes to tamoxifen resistance in breast cancer and is a potential therapeutic that can overcome tamoxifen resistance in breast cancer.
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Affiliation(s)
- Xuemiao Zhang
- Department of Clinical Laboratory, The Third Medical Center of Chinese PLA General Hospital, The Training Site for Postgraduates of Jinzhou Medical University, Jinzhou, 121001, China
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Linfei Huang
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Jing Sun
- China-Japan Union Hospital of Jilin University, Changchun, 130000, China
| | - Jialong Liu
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Yulong Zong
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Luming Wan
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Xiaopan Yang
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Xue Yan
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yanhong Zhang
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Ruzhou Zhao
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Jing Liu
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Hui Zhong
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Congwen Wei
- Beijing Institute of Biotechnology, Beijing, 100071, China
| | - Xiaoli Yang
- Department of Clinical Laboratory, The Third Medical Center of Chinese PLA General Hospital, The Training Site for Postgraduates of Jinzhou Medical University, Jinzhou, 121001, China
- Department of Clinical Laboratory, The Third Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Clinical School of the Third Medical Center of Chinese PLA General Hospital, Anhui Medical University, Hefei, 230032, China
| | - Yanhong Tai
- Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100166, China
| | - Yue Han
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yanhai Wang
- Department of Clinical Laboratory, Huhhot First Hospital, Huhhot, 010030, China.
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Ebata A, Suzuki T, Shoji-Harada N, Hamanaka Y, Miyashita M, Iwabuchi E, Takagi K, Miki Y, Tada H, Ishida T. Immunolocalization of Cytoplasmic ER in ER-negative Breast Carcinoma as a Potent Favorable Prognostic Predictor. Acta Histochem Cytochem 2023; 56:59-66. [PMID: 37680573 PMCID: PMC10480483 DOI: 10.1267/ahc.23-00016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/27/2023] [Indexed: 09/09/2023] Open
Abstract
It is known that estrogen receptor (ER) has extranuclear signaling functions in addition to classical genomic pathway, and estrogenic actions have been reported in ER-negative breast carcinoma cells. However, significance of cytoplasmic-ER immunoreactivity has not been reported in ER-negative breast carcinoma tissues. We immunolocalized cytoplasmic ER in 155 ER-negative breast carcinoma tissues and evaluated its clinicopathological significance including the prognosis. As a comparative cohort set, we also used 142 ER-positive breast carcinomas. Cytoplasmic-ER immunoreactivity was detected in the carcinoma cells, but not in the non-neoplastic mammary epithelium. Cytoplasmic-ER immunoreactivity was positive in the 35 out of 155 (23%) ER-negative breast carcinoma cases, whereas it was detected only in 2 out of 142 (1.4%) ER-positive cases. Cytoplasmic ER status was positively associated with cytoplasmic-PR status, but inversely associated with Ki67 labeling index or distant free-relapse survival rate. Moreover, cytoplasmic-ER status turned out to be an independent good prognostic factor for both distant relapse-free survival and breast cancer specific survival. These findings suggested that cytoplasmic ER plays important roles in the ER-negative breast carcinoma, and cytoplasmic ER is a potent good prognostic factor. Among the ER-negative breast cancer patients, clinical benefit of chemotherapy may be limited in the cytoplasmic-ER positive cases.
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Affiliation(s)
- Akiko Ebata
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980–8574, Japan
| | - Takashi Suzuki
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Pathology, Tohoku University Hospital, Sendai, Japan
| | - Narumi Shoji-Harada
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980–8574, Japan
| | - Yohei Hamanaka
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980–8574, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Minoru Miyashita
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980–8574, Japan
| | - Erina Iwabuchi
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kiyoshi Takagi
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Miki
- Department of Nursing, Faculty of Medical Science and Welfare, Tohoku Bunka Gakuen University, Sendai, Japan
| | - Hiroshi Tada
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980–8574, Japan
| | - Takanori Ishida
- Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980–8574, Japan
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Proteomic Analysis of Human Breast Cancer MCF-7 Cells to Identify Cellular Targets of the Anticancer Pigment OR3 from Streptomyces coelicolor JUACT03. Appl Biochem Biotechnol 2023; 195:236-252. [PMID: 36070163 DOI: 10.1007/s12010-022-04128-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2022] [Indexed: 01/13/2023]
Abstract
Search for ideal compounds with known pathways of anticancer mechanism is still a priority research focus for cancer, as it continues to be a major health challenge across the globe. Hence, in the present study, anticancer potential of a yellow pigment fraction, OR3, isolated from Streptomyces coelicolor JUACT03 was assessed on the breast cancer cell line MCF-7. TLC-fractionated OR3 pigment was subjected to HPLC and GC-MS analysis for characterization and identification of the bioactive component. MCF-7 cells were treated with IC50 concentration of OR3 and the molecular alterations were analyzed using mass spectrometry-based quantitative proteomic analysis. Bioinformatics tools such as STRING analysis and Ingenuity Pathway Analysis were performed to analyze proteomics data and to identify dysregulated signaling pathways. As per our obtained data, OR3 treatment decreased cell proliferation and induced apoptotic cell death due to significant dysregulation of protein expressions in MCF-7 cells. Altered expression included the ribosomal, mRNA processing and vesicle-mediated transport proteins as a result of OR3 treatment. Downregulation of MAPK proteins, NFkB, and estradiol signaling was identified in OR3-treated MCF-7 cells. Mainly eIF2, mTOR, and eIF4 signaling pathways were altered in OR3-treated cells. GC-MS data indicated the presence of novel compounds in OR3 fraction. It can be concluded that OR3 exhibits potent anticancer activity on the breast cancer cells mainly through altering the expression and affecting the signaling proteins which are involved in different cell proliferation/apoptotic pathways thereby causing inhibition of cancer cell proliferation, survival and metastasis.
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9
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Habara M, Shimada M. Estrogen receptor α revised: Expression, structure, function, and stability. Bioessays 2022; 44:e2200148. [PMID: 36192154 DOI: 10.1002/bies.202200148] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/09/2022] [Accepted: 09/09/2022] [Indexed: 11/11/2022]
Abstract
Estrogen receptor α (ERα) is a ligand-dependent transcription factor that regulates the expression of estrogen-responsive genes. Approximately 70% of patients with breast cancer are ERα positive. Estrogen stimulates cancer cell proliferation and contributes to tumor progression. Endocrine therapies, which suppress the ERα signaling pathway, significantly improve the prognosis of patients with breast cancer. However, the development of de novo or acquired endocrine therapy resistance remains a barrier to breast cancer treatment. Therefore, understanding the regulatory mechanisms of ERα is essential to overcome the resistance to treatment. This review focuses on the regulation of ERα expression, including copy number variation, epigenetic regulation, transcriptional regulation, and stability, as well as functions from the point of view post-translational modifications.
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Affiliation(s)
- Makoto Habara
- Department of Veterinary Biochemistry, Yamaguchi University, Yamaguchi, Yamaguchi, Japan
| | - Midori Shimada
- Department of Veterinary Biochemistry, Yamaguchi University, Yamaguchi, Yamaguchi, Japan
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Tecalco-Cruz AC, Ramírez-Jarquín JO, Macías-Silva M, Sosa-Garrocho M, López-Camarillo C. Novel Breast Cancer Treatment by Targeting Estrogen Receptor-Alpha Stability Using Proteolysis-Targeting Chimeras (PROTACs) Technology. Breast Cancer 2022. [DOI: 10.36255/exon-publications-breast-cancer-protacs] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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11
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FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer. Proc Natl Acad Sci U S A 2022; 119:e2110256119. [PMID: 35394865 PMCID: PMC9169630 DOI: 10.1073/pnas.2110256119] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
SignificanceEstrogen receptor α (ERα) is a transcription factor that induces cell proliferation and exhibits increased expression in a large subset of breast cancers. We comprehensively searched for indicators of poor prognosis in ERα-positive breast cancer through the multiple databases, including interactome, transcriptome, and survival analysis, and identified FKBP52. We found that two immunophilins, FKBP52 and FKBP51, have opposing effects on ERα stability and propose that therapeutic targeting of FKBP52 could be useful for the prevention and treatment of ERα-positive breast cancers, including endocrine therapy-resistant breast cancers.
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12
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Tecalco-Cruz AC, Zepeda-Cervantes J, Ramírez-Jarquín JO, Rojas-Ochoa A. Proteolysis-targeting chimeras and their implications in breast cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:496-510. [PMID: 36046115 PMCID: PMC9400758 DOI: 10.37349/etat.2021.00060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/12/2021] [Indexed: 12/14/2022] Open
Abstract
Breast cancer (BC) is a highly heterogeneous neoplasm of the mammary tissue, causing the deaths of a large number of women worldwide. Nearly 70% and 20% of BC cases are estrogen receptor alpha positive (ERα+) and human epidermal growth factor receptor 2-positive (HER2+), respectively; therefore, ER and HER2 targeted therapies have been employed in BC treatment. However, resistance to these therapies has been reported, indicating a need for developing novel therapeutic strategies. Proteolysis-targeting chimeras (PROTACs) are new, promising therapeutic tools designed with a bimodular structure: one module allows specific binding to target proteins, and the other module allows efficient degradation of these target proteins. In this paper, PROTACs and their potential in controlling the progression of ERα and HER2+ BC are discussed.
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Affiliation(s)
- Angeles C. Tecalco-Cruz
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), CDMX, Mexico City 03100, Mexico
| | - Jesús Zepeda-Cervantes
- Departamento de Microbiología e Inmunología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México (UNAM), CDMX, Mexico City 04510, Mexico
| | - Josué O. Ramírez-Jarquín
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), CDMX, Mexico City 04500, Mexico
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13
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Cirillo F, Pellegrino M, Talia M, Perrotta ID, Rigiracciolo DC, Spinelli A, Scordamaglia D, Muglia L, Guzzi R, Miglietta AM, De Francesco EM, Belfiore A, Maggiolini M, Lappano R. Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts. Clin Transl Med 2021; 11:e516. [PMID: 34841688 PMCID: PMC8567034 DOI: 10.1002/ctm2.516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild-type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC-1) is characterized by a unique expression of 46 kDa ERα splice variant (ERα46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ERα46 and IR occurs in BCAHC-1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high-throughput RNA sequencing analysis, we have also found that the cytokine interleukin-11 (IL11) is the main factor linking BCAHC-1 cells to breast cancer-associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC-1 cells regulates pro-tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM-1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC.
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Affiliation(s)
- Francesca Cirillo
- Department of PhysicsUniversity of CalabriaRendeItaly
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Michele Pellegrino
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Marianna Talia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Ida Daniela Perrotta
- Centre for Microscopy and Microanalysis, Transmission Electron Microscopy Laboratory, and Department of Biology, Ecology and Earth SciencesUniversity of CalabriaRendeItaly
| | | | - Asia Spinelli
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Domenica Scordamaglia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Lucia Muglia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Rita Guzzi
- Department of PhysicsUniversity of CalabriaRendeItaly
| | | | | | - Antonino Belfiore
- Department of Clinical and Experimental Medicine, University of CataniaGaribaldi‐Nesima HospitalCataniaItaly
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
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14
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Estrogenic hormones receptors in Alzheimer's disease. Mol Biol Rep 2021; 48:7517-7526. [PMID: 34657250 DOI: 10.1007/s11033-021-06792-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/15/2021] [Indexed: 02/06/2023]
Abstract
Estrogens are hormones that play a critical role during development and growth for the adequate functioning of the reproductive system of women, as well as for maintaining bones, metabolism, and cognition. During menopause, the levels of estrogens are decreased, altering their signaling mediated by their intracellular receptors such as estrogen receptor alpha and beta (ERα and ERβ), and G protein-coupled estrogen receptor (GPER). In the brain, the reduction of molecular pathways mediated by estrogenic receptors seems to favor the progression of Alzheimer's disease (AD) in postmenopausal women. In this review, we investigate the participation of estrogen receptors in AD in women during aging.
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15
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Li K, Liu T. Evaluation of Oncogene NUP37 as a Potential Novel Biomarker in Breast Cancer. Front Oncol 2021; 11:669655. [PMID: 34386417 PMCID: PMC8353244 DOI: 10.3389/fonc.2021.669655] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 07/12/2021] [Indexed: 11/26/2022] Open
Abstract
Purpose There is an urgent need to identify oncogenes that may be beneficial to diagnose and develop target therapy for breast cancer. Methods Based on the GEO database, DECenter was used to screen the differentially overexpressed genes in breast cancer samples. Search Tool for the Retrieval of Interacting Genes and Cytoscape were performed to construct the PPI network to predict the hub gene. Functional and pathway enrichment were performed based on GO analysis. GEO2R, Oncomine, human tissue microarray staining, and western blot were applied to confirm the expression of NUP37. The association between NUP37 expression and prognosis in patients with breast cancer were assessed using the Kaplan–Meier plotter online tool and OncoLnc. siRNAs were used to knock down NUP37 and evaluate proliferation, migration, and stemness in breast cancer cells. Results We found that 138 genes were differentially upregulated in breast cancer samples, mainly comprising components of the nucleus and involved in the cell cycle process. NUP37 was identified as a hub gene that is upregulated in breast cancer patients related to a significantly worse survival rate. Furthermore, we confirmed that the downregulation of NUP37 in breast cancer cells results in the inhibition of cell growth, migration, and stemness. Conclusions High expression of NUP37 in breast cancer patients is associated with a poorer prognosis and promotion of cell growth, migration, and stemness. The multiple bioinformatics and experimental analysis help provide a comprehensive understanding of the roles of NUP37 as a potential marker for diagnosis and prognosis and as a novel therapeutic target in breast cancer.
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Affiliation(s)
- Kangdi Li
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Liu
- The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Wang X, Yang D. The regulation of RNA metabolism in hormone signaling and breast cancer. Mol Cell Endocrinol 2021; 529:111221. [PMID: 33711334 PMCID: PMC8262629 DOI: 10.1016/j.mce.2021.111221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 02/09/2021] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
As the most frequent women's cancer, breast cancer causes the second most cancer-related death in women worldwide. Majority of the breast cancers are hormone receptor-positive and commonly treated by hormone therapy. Thus, the expression levels of hormone receptors signaling pathways are pivotal in the development and therapy of breast cancer. The expression of hormone receptors signaling pathways is not only regulated at the transcription level but also at the post-transcription level by both proteins and RNAs. In addition to that, the function of hormone receptors can also be regulated by RNAs. In this review, we summarize the roles of RNAs in hormone receptor-positive breast cancer. We introduce how mRNA stability and protein function of genes in hormone receptors signaling pathways are regulated by RNA-binding proteins, miRNAs, and lncRNAs. We believe these proteins and RNAs can be potential therapeutic targets of breast cancer.
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Affiliation(s)
- Xiaofei Wang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, PA, 15261, USA
| | - Da Yang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, PA, 15261, USA; UPMC Hillman Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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17
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Díaz M, Lobo F, Hernández D, Amesty Á, Valdés-Baizabal C, Canerina-Amaro A, Mesa-Herrera F, Soler K, Boto A, Marín R, Estévez-Braun A, Lahoz F. FLTX2: A Novel Tamoxifen Derivative Endowed with Antiestrogenic, Fluorescent, and Photosensitizer Properties. Int J Mol Sci 2021; 22:ijms22105339. [PMID: 34069498 PMCID: PMC8161337 DOI: 10.3390/ijms22105339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/28/2021] [Accepted: 05/08/2021] [Indexed: 11/16/2022] Open
Abstract
Tamoxifen is the most widely used selective modulator of estrogen receptors (SERM) and the first strategy as coadjuvant therapy for the treatment of estrogen-receptor (ER) positive breast cancer worldwide. In spite of such success, tamoxifen is not devoid of undesirable effects, the most life-threatening reported so far affecting uterine tissues. Indeed, tamoxifen treatment is discouraged in women under risk of uterine cancers. Recent molecular design efforts have endeavoured the development of tamoxifen derivatives with antiestrogen properties but lacking agonistic uterine tropism. One of this is FLTX2, formed by the covalent binding of tamoxifen as ER binding core, 7-nitrobenzofurazan (NBD) as the florescent dye, and Rose Bengal (RB) as source for reactive oxygen species. Our analyses demonstrate (1) FLTX2 is endowed with similar antiestrogen potency as tamoxifen and its predecessor FLTX1, (2) shows a strong absorption in the blue spectral range, associated to the NBD moiety, which efficiently transfers the excitation energy to RB through intramolecular FRET mechanism, (3) generates superoxide anions in a concentration- and irradiation time-dependent process, and (4) Induces concentration- and time-dependent MCF7 apoptotic cell death. These properties make FLTX2 a very promising candidate to lead a novel generation of SERMs with the endogenous capacity to promote breast tumour cell death in situ by photosensitization.
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Affiliation(s)
- Mario Díaz
- Departamento Biología Animal, Edafología y Geología, Universidad de La Laguna, 38200 Tenerife, Spain;
- Unidad Asociada ULL-CSIC “Fisiología y Biofísica de la Membrana Celular en Enfermedades Neurodegenerativas y Tumorales”, 38200 Tenerife, Spain; (A.B.); (R.M.); (F.L.)
- Correspondence:
| | - Fernando Lobo
- Programa Agustín de Betancourt, Universidad de la Laguna, 38200 Tenerife, Spain; (F.L.); (Á.A.); (C.V.-B.)
| | - Dácil Hernández
- Instituto de Productos Naturales y Agrobiología del CSIC, Avda. Astrofísico F. Sánchez, 38206 Tenerife, Spain;
| | - Ángel Amesty
- Programa Agustín de Betancourt, Universidad de la Laguna, 38200 Tenerife, Spain; (F.L.); (Á.A.); (C.V.-B.)
- Instituto Universitario de Bioorgánica “Antonio González”, Universidad de La Laguna, 38200 Tenerife, Spain;
| | - Catalina Valdés-Baizabal
- Programa Agustín de Betancourt, Universidad de la Laguna, 38200 Tenerife, Spain; (F.L.); (Á.A.); (C.V.-B.)
- Departamento Ciencias Médicas Básicas, Universidad de La Laguna, 38200 Tenerife, Spain;
| | - Ana Canerina-Amaro
- Departamento Ciencias Médicas Básicas, Universidad de La Laguna, 38200 Tenerife, Spain;
| | - Fátima Mesa-Herrera
- Departamento Biología Animal, Edafología y Geología, Universidad de La Laguna, 38200 Tenerife, Spain;
| | - Kevin Soler
- Departamento Física, IUdEA, Universidad de La Laguna, 38200 Tenerife, Spain;
| | - Alicia Boto
- Unidad Asociada ULL-CSIC “Fisiología y Biofísica de la Membrana Celular en Enfermedades Neurodegenerativas y Tumorales”, 38200 Tenerife, Spain; (A.B.); (R.M.); (F.L.)
- Instituto de Productos Naturales y Agrobiología del CSIC, Avda. Astrofísico F. Sánchez, 38206 Tenerife, Spain;
| | - Raquel Marín
- Unidad Asociada ULL-CSIC “Fisiología y Biofísica de la Membrana Celular en Enfermedades Neurodegenerativas y Tumorales”, 38200 Tenerife, Spain; (A.B.); (R.M.); (F.L.)
- Departamento Ciencias Médicas Básicas, Universidad de La Laguna, 38200 Tenerife, Spain;
| | - Ana Estévez-Braun
- Instituto Universitario de Bioorgánica “Antonio González”, Universidad de La Laguna, 38200 Tenerife, Spain;
- Departamento Química Orgánica, Universidad de La Laguna, 38200 Tenerife, Spain
| | - Fernando Lahoz
- Unidad Asociada ULL-CSIC “Fisiología y Biofísica de la Membrana Celular en Enfermedades Neurodegenerativas y Tumorales”, 38200 Tenerife, Spain; (A.B.); (R.M.); (F.L.)
- Departamento Física, IUdEA, Universidad de La Laguna, 38200 Tenerife, Spain;
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18
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Al-kuraishy HM, Al-Gareeb AI, Faidah H, Al-Maiahy TJ, Cruz-Martins N, Batiha GES. The Looming Effects of Estrogen in Covid-19: A Rocky Rollout. Front Nutr 2021; 8:649128. [PMID: 33816542 PMCID: PMC8012689 DOI: 10.3389/fnut.2021.649128] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 02/15/2021] [Indexed: 12/17/2022] Open
Abstract
In the face of the Covid-19 pandemic, an intensive number of studies have been performed to understand in a deeper way the mechanisms behind better or worse clinical outcomes. Epidemiologically, men subjects are more prone to severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infections than women, with a similar scenario being also stated to the previous coronavirus diseases, namely, SARS-CoV in 2003 and Middle East Respiratory Syndrome coronavirus diseases (MERS-CoV) in 2012. In addition, and despite that aging is regarded as an independent risk factor for the severe form of the disease, even so, women protection is evident. In this way, it has been expected that sex hormones are the main determinant factors in gender differences, with the immunomodulatory effects of estrogen in different viral infections, chiefly in Covid-19, attracting more attention as it might explain the case-fatality rate and predisposition of men for Covid-19 severity. Here, we aim to provide a mini-review and an overview on the protective effects of estrogen in Covid-19. Different search strategies were performed including Scopus, Web of Science, Medline, Pubmed, and Google Scholar database to find relative studies. Findings of the present study illustrated that women have a powerful immunomodulating effect against Covid-19 through the effect of estrogen. This study illustrates that estrogens have noteworthy anti-inflammatory and immuno-modulatory effects in Covid-19. Also, estrogen hormone reduces SARS-CoV-2 infectivity through modulation of pro-inflammatory signaling pathways. This study highlighted the potential protective effect of estrogen against Covid-19 and recommended for future clinical trial and prospective studies to elucidate and confirm this protective effect.
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Affiliation(s)
- Hayder M. Al-kuraishy
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Hani Faidah
- Microbiology, Faculty of Medicine, Umm Al Qura University, Mecca, Saudi Arabia
| | - Thabat J. Al-Maiahy
- Department of Gynecology and Obstetrics, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
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19
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Pathological Maintenance and Evolution of Breast Cancer: The Convergence of Irreversible Biological Actions of ER Alpha. ENDOCRINES 2020. [DOI: 10.3390/endocrines2010001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Estrogen receptor alpha (ERα) is a modulator of breast cancer maintenance and evolution. Hence, analysis of underlying mechanisms by which ERα operates is of importance for the improvement of the hormonal therapy of the disease. This review focuses on the irreversible character of the mechanism of action of ERα, which also concerns other members of the steroid hormones receptors family. ERα moves in permanence between targets localized especially at the chromatin level to accomplish gene transcriptions imposed by the estrogenic ligands and specific antagonists. Receptor association as at the plasma membrane, where it interacts with other recruitment sites, extends its regulatory potency to growth factors and related peptides through activation of signal transductions pathways. If the latter procedure is suitable for the transcriptions in which the receptor operates as a coregulator of another transcription factor, it is of marginal influence with regard to the direct estrogenic regulation procedure, especially in the context of the present review. Irreversibility of the successive steps of the underlying transcription cycle guarantees maintenance of homeostasis and evolution according to vital necessities. To justify this statement, reported data are essentially described in a holistic view rather than in the context of exhaustive analysis of a molecular event contributing to a specific function as well as in a complementary perspective to elaborate new therapeutic approaches with antagonistic potencies against those tumors promoting ERα properties.
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20
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Zattarin E, Leporati R, Ligorio F, Lobefaro R, Vingiani A, Pruneri G, Vernieri C. Hormone Receptor Loss in Breast Cancer: Molecular Mechanisms, Clinical Settings, and Therapeutic Implications. Cells 2020; 9:cells9122644. [PMID: 33316954 PMCID: PMC7764472 DOI: 10.3390/cells9122644] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/02/2020] [Accepted: 12/05/2020] [Indexed: 12/14/2022] Open
Abstract
Hormone receptor-positive breast cancer (HR+ BC) accounts for approximately 75% of new BC diagnoses. Despite the undisputable progresses obtained in the treatment of HR+ BC in recent years, primary or acquired resistance to endocrine therapies still represents a clinically relevant issue, and is largely responsible for disease recurrence after curative surgery, as well as for disease progression in the metastatic setting. Among the mechanisms causing primary or acquired resistance to endocrine therapies is the loss of estrogen/progesterone receptor expression, which could make BC cells independent of estrogen stimulation and, consequently, resistant to estrogen deprivation or the pharmacological inhibition of estrogen receptors. This review aims at discussing the molecular mechanisms and the clinical implications of HR loss as a result of the therapies used in the neoadjuvant setting or for the treatment of advanced disease in HR+ BC patients.
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Affiliation(s)
- Emma Zattarin
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy; (E.Z.); (R.L.); (F.L.); (R.L.); (A.V.); (G.P.)
| | - Rita Leporati
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy; (E.Z.); (R.L.); (F.L.); (R.L.); (A.V.); (G.P.)
| | - Francesca Ligorio
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy; (E.Z.); (R.L.); (F.L.); (R.L.); (A.V.); (G.P.)
| | - Riccardo Lobefaro
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy; (E.Z.); (R.L.); (F.L.); (R.L.); (A.V.); (G.P.)
| | - Andrea Vingiani
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy; (E.Z.); (R.L.); (F.L.); (R.L.); (A.V.); (G.P.)
| | - Giancarlo Pruneri
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy; (E.Z.); (R.L.); (F.L.); (R.L.); (A.V.); (G.P.)
- Department of Oncology and Haematology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Claudio Vernieri
- Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy; (E.Z.); (R.L.); (F.L.); (R.L.); (A.V.); (G.P.)
- IFOM, The FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
- Correspondence: ; Tel.: +39-02-2390-3650
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21
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Bischoff P, Kornhuber M, Dunst S, Zell J, Fauler B, Mielke T, Taubenberger AV, Guck J, Oelgeschläger M, Schönfelder G. Estrogens Determine Adherens Junction Organization and E-Cadherin Clustering in Breast Cancer Cells via Amphiregulin. iScience 2020; 23:101683. [PMID: 33163938 PMCID: PMC7607435 DOI: 10.1016/j.isci.2020.101683] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/18/2020] [Accepted: 10/12/2020] [Indexed: 12/17/2022] Open
Abstract
Estrogens play an important role in the development and progression of human cancers, particularly in breast cancer. Breast cancer progression depends on the malignant destabilization of adherens junctions (AJs) and disruption of tissue integrity. We found that estrogen receptor alpha (ERα) inhibition led to a striking spatial reorganization of AJs and microclustering of E-Cadherin (E-Cad) in the cell membrane of breast cancer cells. This resulted in increased stability of AJs and cell stiffness and a reduction of cell motility. These effects were actomyosin-dependent and reversible by estrogens. Detailed investigations showed that the ERα target gene and epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) essentially regulates AJ reorganization and E-Cad microclustering. Our results not only describe a biological mechanism for the organization of AJs and the modulation of mechanical properties of cells but also provide a new perspective on how estrogens and anti-estrogens might influence the formation of breast tumors.
ERα inhibition causes adherens junction (AJ) reorganization through AREG and EGFR AJ reorganization coincides with microclustering of E-Cadherin at cell membranes AJ reorganization and microclustering of E-Cadherin are actomyosin dependent AJ reorganization correlates with increased cell stiffness and reduced motility
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Affiliation(s)
- Philip Bischoff
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Straße 8-10, 10589 Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Marja Kornhuber
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Straße 8-10, 10589 Berlin, Germany.,Freie Universität Berlin, 14195 Berlin, Germany
| | - Sebastian Dunst
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Straße 8-10, 10589 Berlin, Germany
| | - Jakob Zell
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Straße 8-10, 10589 Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Beatrix Fauler
- Max Planck Institute for Molecular Genetics, Microscopy and Cryo-Electron Microscopy Service Group, 14195 Berlin, Germany
| | - Thorsten Mielke
- Max Planck Institute for Molecular Genetics, Microscopy and Cryo-Electron Microscopy Service Group, 14195 Berlin, Germany
| | - Anna V Taubenberger
- Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany
| | - Jochen Guck
- Max Planck Institute for the Science of Light, Max-Planck-Zentrum für Physik und Medizin, 91058 Erlangen, Germany
| | - Michael Oelgeschläger
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Straße 8-10, 10589 Berlin, Germany
| | - Gilbert Schönfelder
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Straße 8-10, 10589 Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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22
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TRIM11 promotes breast cancer cell proliferation by stabilizing estrogen receptor α. Neoplasia 2020; 22:343-351. [PMID: 32599554 PMCID: PMC7326724 DOI: 10.1016/j.neo.2020.06.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/01/2020] [Accepted: 06/05/2020] [Indexed: 01/17/2023] Open
Abstract
Breast cancer is the most commonly diagnosed malignancy in female worldwide, over 70% of which are estrogen receptor α (ERα) positive. ERα has a crucial role in the initiation and progression of breast cancer and is an indicator of endocrine therapy, while endocrine resistance is an urgent problem in ER-positive breast cancer patients. In the present study, we identify a novel E3 ubiquitin ligase TRIM11 function to facilitate ERα signaling. TRIM11 is overexpressed in human breast cancer, and associates with poor prognosis. The protein level of TRIM11 is highly correlated with ERα. RNA-seq results suggest that ERα signaling may be an underlying target of TRIM11. Depletion of TRIM11 in breast cancer cells significantly decreases cell proliferation and migration. And the suppression effects can be reversed by overexpressing ERα. In addition, ERα protein level, ERα target genes expression and estrogen response element activity are also dramatically decreased by TRIM11 depletion. Further mechanistic analysis indicates that the RING domain of TRIM11 interacted with the N terminal of ERα in the cytoplasm and promotes its mono-ubiquitination, thus enhances ERα protein stability. Our study describes TRIM11 as a modulating factor of ERα and increases ERα stability via mono-ubiquitination. TRIM11 could be a promising therapeutic target for breast cancer treatment.
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23
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Quicker, deeper and stronger imaging: A review of tumor-targeted, near-infrared fluorescent dyes for fluorescence guided surgery in the preclinical and clinical stages. Eur J Pharm Biopharm 2020; 152:123-143. [PMID: 32437752 DOI: 10.1016/j.ejpb.2020.05.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 05/03/2020] [Accepted: 05/03/2020] [Indexed: 12/12/2022]
Abstract
Cancer is a public health problem and the main cause of human mortality and morbidity worldwide. Complete removal of tumors and metastatic lymph nodes in surgery is significantly beneficial for the prognosis of patients. Tumor-targeted, near-infrared fluorescent (NIRF) imaging is an emerging field of real-time intraoperative cancer imaging based on tumor-targeted NIRF dyes. Targeted NIRF dyes contain NIRF fluorophores and specific binding ligands such as antibodies, peptides and small molecules. The present article reviews recently updated tumor-targeted NIRF dyes for the molecular imaging of malignant tumors in the preclinical stage and clinical trials. The strengths and challenges of NIRF agents with tumor-targeting ability are also summarized. Smaller ligands, near infrared II dyes, dual-modality dyes and activatable dyes may contribute to quicker, deeper, stronger imaging in the nearest future. In this review, we highlighted tumor-targeted NIRF dyes for fluorescence-guided surgery and their potential clinical translation.
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Sirt3 Exerts Its Tumor-Suppressive Role by Increasing p53 and Attenuating Response to Estrogen in MCF-7 Cells. Antioxidants (Basel) 2020; 9:antiox9040294. [PMID: 32244715 PMCID: PMC7222218 DOI: 10.3390/antiox9040294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/21/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Estrogen (E2) is a major risk factor for the initiation and progression of malignancy in estrogen receptor (ER) positive breast cancers, whereas sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, has the inhibitory effect on the tumorigenic properties of ER positive MCF-7 breast cancer cells. Since it is unclear if this effect is mediated through the estrogen receptor alpha (ERα) signaling pathway, in this study, we aimed to determine if the tumor-suppressive function of Sirt3 in MCF-7 cells interferes with their response to E2. Although we found that Sirt3 improves the antioxidative response and mitochondrial fitness of the MCF-7 cells, it also increases DNA damage along with p53, AIF, and ERα expression. Moreover, Sirt3 desensitizes cells to the proliferative effect of E2, affects p53 by disruption of the ERα–p53 interaction, and decreases proliferation, colony formation, and migration of the cells. Our observations indicate that these tumor-suppressive effects of Sirt3 could be reversed by E2 treatment only to a limited extent which is not sufficient to recover the tumorigenic properties of the MCF-7 cells. This study provides new and interesting insights with respect to the functional role of Sirt3 in the E2-dependent breast cancers.
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Kondakova IV, Shashova EE, Sidenko EA, Astakhova TM, Zakharova LA, Sharova NP. Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation. Biomolecules 2020; 10:biom10040500. [PMID: 32224970 PMCID: PMC7226411 DOI: 10.3390/biom10040500] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/21/2020] [Accepted: 03/25/2020] [Indexed: 12/11/2022] Open
Abstract
This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of proteasomes and mechanisms of protein ubiquitination and cleavage are described. According to the modern concept, the ubiquitin proteasome system (UPS) is involved in the regulation of the activity of ERs in several ways. First, UPS performs the ubiquitination of ERs with a change in their functional activity. Second, UPS degrades ERs and their transcriptional regulators. Third, UPS affects the expression of ER genes. In addition, the opportunity of the regulation of proteasome functioning by ERs—in particular, the expression of immune proteasomes—is discussed. Understanding the complex mechanisms underlying the regulation of ERs and proteasomes has great prospects for the development of new therapeutic agents that can make a significant contribution to the treatment of diseases associated with the impaired function of these biomolecules.
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Affiliation(s)
- Irina V. Kondakova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, 634009 Tomsk, Russia; (I.V.K.); (E.E.S.); (E.A.S.)
| | - Elena E. Shashova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, 634009 Tomsk, Russia; (I.V.K.); (E.E.S.); (E.A.S.)
| | - Evgenia A. Sidenko
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, 634009 Tomsk, Russia; (I.V.K.); (E.E.S.); (E.A.S.)
| | - Tatiana M. Astakhova
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia; (T.M.A.); (L.A.Z.)
| | - Liudmila A. Zakharova
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia; (T.M.A.); (L.A.Z.)
| | - Natalia P. Sharova
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia; (T.M.A.); (L.A.Z.)
- Correspondence: ; Tel.: +7-499-135-7674; Fax: +7-499-135-3322
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Rodriguez AC, Vahrenkamp JM, Berrett KC, Clark KA, Guillen KP, Scherer SD, Yang CH, Welm BE, Janát-Amsbury MM, Graves BJ, Gertz J. ETV4 Is Necessary for Estrogen Signaling and Growth in Endometrial Cancer Cells. Cancer Res 2020; 80:1234-1245. [PMID: 32046982 PMCID: PMC7073291 DOI: 10.1158/0008-5472.can-19-1382] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 12/09/2019] [Accepted: 01/15/2020] [Indexed: 11/16/2022]
Abstract
Estrogen signaling through estrogen receptor alpha (ER) plays a major role in endometrial cancer risk and progression, however, the molecular mechanisms underlying ER's regulatory role in endometrial cancer are poorly understood. In breast cancer cells, ER genomic binding is enabled by FOXA1 and GATA3, but the transcription factors that control ER genomic binding in endometrial cancer cells remain unknown. We previously identified ETV4 as a candidate factor controlling ER genomic binding in endometrial cancer cells, and here we explore the functional importance of ETV4. Homozygous deletion of ETV4, using CRISPR/Cas9, led to greatly reduced ER binding at the majority of loci normally bound by ER. Consistent with the dramatic loss of ER binding, the gene expression response to estradiol was dampened for most genes. ETV4 contributes to estrogen signaling in two distinct ways. ETV4 loss affects chromatin accessibility at some ER bound loci and impairs ER nuclear translocation. The diminished estrogen signaling upon ETV4 deletion led to decreased growth, particularly in 3D culture, where hollow organoids were formed and in vivo in the context of estrogen-dependent growth. These results show that ETV4 plays an important role in estrogen signaling in endometrial cancer cells. SIGNIFICANCE: Estrogen receptor alpha (ER) is a key oncogene in endometrial cancer. This study uncovers ETV4 as an important factor in controlling the activity of ER and the growth of endometrial cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/6/1234/F1.large.jpg.
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Affiliation(s)
- Adriana C Rodriguez
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Jeffery M Vahrenkamp
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Kristofer C Berrett
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Kathleen A Clark
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Katrin P Guillen
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Sandra D Scherer
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Chieh-Hsiang Yang
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah
- Department of Bioengineering, University of Utah, Salt Lake City, Utah
| | - Bryan E Welm
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
- Department of Surgery, University of Utah, Salt Lake City, Utah
| | - Margit M Janát-Amsbury
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah
- Department of Bioengineering, University of Utah, Salt Lake City, Utah
| | - Barbara J Graves
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
- Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Jason Gertz
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah.
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
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27
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Guo Z, Tada H, Kitamura N, Hamada Y, Miyashita M, Harada-Shoji N, Sato A, Hamanaka Y, Tsuboi K, Harada N, Takano-Kasuya M, Okada H, Nakano Y, Ohuchi N, Hayashi SI, Ishida T, Gonda K. Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR +/HER2 - Breast Cancer. Cancers (Basel) 2019; 11:cancers11040526. [PMID: 31013810 PMCID: PMC6520781 DOI: 10.3390/cancers11040526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 04/01/2019] [Accepted: 04/09/2019] [Indexed: 11/26/2022] Open
Abstract
In addition to genomic signaling, Estrogen receptor alpha (ERα) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ERα and ET resistance has not been extensively studied. We sought to measure extranuclear ERα expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ERα by IHC-PIDs in vitro, we developed “the nearest-neighbor method” to calculate the extranuclear ERα. Furthermore, tissue sections from 65 patients with HR+/HER2- BC were examined by IHC-PIDs, and the total ERα, nuclear ERα, extranuclear ERα PIDs score, and ratio of extranuclear-to-nuclear ERα (ENR) were measured using the novel method. We demonstrate that quantification of ERα using IHC-PIDs exhibited strong correlations to real-time qRT-PCR (r2 = 0.94) and flow cytometry (r2 = 0.98). High ERα ENR was significantly associated with poor overall survival (p = 0.048) and disease-free survival (DFS) (p = 0.007). Multivariate analysis revealed that the ERα ENR was an independent prognostic factor for DFS [hazard ratio, 3.8; 95% CI, 1.4–11.8; p = 0.006]. Our automated measurement has high accuracy to localize and assess extranuclear ERα. A high ERα ENR in HR+/HER2− BC indicates decreased likelihood of benefiting from ET.
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Affiliation(s)
- Zhaorong Guo
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Hiroshi Tada
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Narufumi Kitamura
- Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Yoh Hamada
- Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Minoru Miyashita
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Narumi Harada-Shoji
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Akiko Sato
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Yohei Hamanaka
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Kouki Tsuboi
- Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Nobuhisa Harada
- Bio Systems Development Group, Bio Advanced Technology Division, Corporate R&D Headquarters, KONICA MINOLTA, INC., Hino, Tokyo 191-8511, Japan.
| | - Mayumi Takano-Kasuya
- Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Hisatake Okada
- Bio Systems Development Group, Bio Advanced Technology Division, Corporate R&D Headquarters, KONICA MINOLTA, INC., Hino, Tokyo 191-8511, Japan.
| | - Yasushi Nakano
- Bio Systems Development Group, Bio Advanced Technology Division, Corporate R&D Headquarters, KONICA MINOLTA, INC., Hino, Tokyo 191-8511, Japan.
| | - Noriaki Ohuchi
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Shin-Ichi Hayashi
- Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Takanori Ishida
- Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
| | - Kohsuke Gonda
- Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
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Tecalco-Cruz AC, Ramírez-Jarquín JO, Cruz-Ramos E. Estrogen Receptor Alpha and its Ubiquitination in Breast Cancer Cells. Curr Drug Targets 2019; 20:690-704. [DOI: 10.2174/1389450119666181015114041] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/09/2018] [Accepted: 10/09/2018] [Indexed: 12/23/2022]
Abstract
More than 70% of all breast cancer cases are estrogen receptor alpha-positive (ERα). ERα is a member of the nuclear receptor family, and its activity is implicated in the gene transcription linked to the proliferation of breast cancer cells, as well as in extranuclear signaling pathways related to the development of resistance to endocrine therapy. Protein-protein interactions and posttranslational modifications of ERα underlie critical mechanisms that modulate its activity. In this review, the relationship between ERα and ubiquitin protein (Ub), was investigated in the context of breast cancer cells. Interestingly, Ub can bind covalently or non-covalently to ERα resulting in either a proteolytic or non-proteolytic fate for this receptor. Thereby, Ub-dependent molecular pathways that modulate ERα signaling may play a central role in breast cancer progression, and consequently, present critical targets for treatment of this disease.
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Affiliation(s)
- Angeles C. Tecalco-Cruz
- Instituto de Investigaciones Biomedicas. Universidad Nacional Autonoma de Mexico. Mexico City, 04510, Mexico
| | - Josué O. Ramírez-Jarquín
- Instituto de Fisiologia Celular. Universidad Nacional Autonoma de Mexico. Mexico City, 04510, Mexico
| | - Eduardo Cruz-Ramos
- Instituto de Investigaciones Biomedicas. Universidad Nacional Autonoma de Mexico. Mexico City, 04510, Mexico
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Cruz-Ramos E, Sandoval-Hernández A, Tecalco-Cruz AC. Differential expression and molecular interactions of chromosome region maintenance 1 and calreticulin exportins in breast cancer cells. J Steroid Biochem Mol Biol 2019; 185:7-16. [PMID: 29981820 DOI: 10.1016/j.jsbmb.2018.07.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 06/29/2018] [Accepted: 07/04/2018] [Indexed: 12/20/2022]
Abstract
Chromosome region maintenance 1 (CRM-1) and calreticulin (CALR) are two proteins that act as exportins for some nuclear receptors, in addition to other critical functions for cellular homeostasis. In several cancer types, CRM-1 and CALR are upregulated suggesting an imbalance in their functions. However, the regulation of CRM-1 and CALR, and their biological implications, are not completely known. Here, we evaluated the interplay between the levels of CRM-1 and CALR, and estrogen receptor alpha (ERα) status, in breast cancer cells. CRM-1 and CALR were upregulated in mammary tumors relative to normal mammary tissue. Furthermore, the mRNA and protein levels of CRM-1 and CALR were higher in breast cancer cells lacking ERα, in comparison with those that express ERα. Additionally, both proteins were distributed in the nucleus and cytoplasm in the two cell types. Importantly, we identified novel interactions for these exportins. First, we showed an interaction between CRM-1 and CALR, and then we identified that SUN1 and SUN2, two proteins localized in the nuclear envelop, were able to interact specifically with CRM-1, but not CALR. Interestingly, SUN1 and SUN2 expression seemed to be decreased in breast cancer, thereby affecting the interactions of these proteins with CRM-1, and possibly its actions as an exportin. Thus, our data suggest that expression levels for CRM-1 and CALR, the interaction between these exportins, and specific interactions of SUN1 and SUN2 with CRM-1 but not CALR, may be central elements in nucleo-cytoplasmic transport. Furthermore, deregulation of these elements may have serious implications in the progression of breast and other types of cancer.
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Affiliation(s)
- Eduardo Cruz-Ramos
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apdo Postal, México D.F. 04510, Mexico
| | - Antonio Sandoval-Hernández
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apdo Postal, México D.F. 04510, Mexico
| | - Angeles C Tecalco-Cruz
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apdo Postal, México D.F. 04510, Mexico.
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Tecalco-Cruz AC, Cortés-González CC, Cruz-Ramos E, Ramírez Jarquín JO, Romero-Mandujano AK, Sosa-Garrocho M. Interplay between interferon-stimulated gene 15/ISGylation and interferon gamma signaling in breast cancer cells. Cell Signal 2018; 54:91-101. [PMID: 30500379 DOI: 10.1016/j.cellsig.2018.11.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 11/25/2018] [Accepted: 11/26/2018] [Indexed: 12/11/2022]
Abstract
Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein that conjugates to its target proteins to modify them through ISGylation, but the relevance of ISG15 expression and its effects have been not completely defined. Herein, we examined the interplay between ISG15/ISGylation and the interferon-gamma (IFN-γ) signaling pathway in mammary tumors and compared it with that in normal mammary tissues. Our results indicated that mammary tumors had higher levels of ISG15 mRNA and ISG15 protein than the adjacent normal mammary tissue. Furthermore, the expression of IFN-γ signaling components was altered in breast cancer. Interestingly, IFN-γ treatment induced morphological changes in MCF-7 and MDA-MB-231 breast cancer cell lines due to cytoskeletal reorganization. This cellular process seems to be related to the increase in ISGylation of cytoplasmic IQ Motif Containing GTPase Activating Protein 1 (IQGAP1). Interactome analysis also indicated that IFN-γ signaling and the ISGylation system are associated with several proteins implicated in cytoskeletal remodeling, including IQGAP1. Thus, ISG15 may present a potential biomarker for breast cancer, and IFN-γ signaling and protein ISGylation may participate in the regulation of the cytoskeleton in breast cancer cells.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
| | - Carlo César Cortés-González
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Tlalpan, C.P. 14080 Mexico City, Mexico
| | - Eduardo Cruz-Ramos
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Josué O Ramírez Jarquín
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Aline Kay Romero-Mandujano
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Tlalpan, C.P. 14080 Mexico City, Mexico
| | - Marcela Sosa-Garrocho
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
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Tecalco-Cruz AC, Ramírez-Jarquín JO. Polyubiquitination inhibition of estrogen receptor alpha and its implications in breast cancer. World J Clin Oncol 2018; 9:60-70. [PMID: 30148069 PMCID: PMC6107474 DOI: 10.5306/wjco.v9.i4.60] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/22/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Estrogen receptor alpha (ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear activity of ERα is related to endocrine therapy resistance. ERα polyubiquitination is induced by the estradiol hormone, and also by selective estrogen receptor degraders, resulting in ERα degradation via the ubiquitin proteasome system. Moreover, polyubiquitination is related to the ERα transcription cycle, and some E3-ubiquitin ligases also function as coactivators for ERα. Several studies have demonstrated that ERα polyubiquitination is inhibited by multiple mechanisms that include posttranslational modifications, interactions with coregulators, and formation of specific protein complexes with ERα. These events are responsible for an increase in ERα protein levels and deregulation of its signaling in breast cancers. Thus, ERα polyubiquitination inhibition may be a key factor in the progression of breast cancer and resistance to endocrine therapy.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Programa de Investigación de Cáncer de Mama (PICM), Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México 04510, México
| | - Josué O Ramírez-Jarquín
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México 04510, México
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Protein ISGylation and free ISG15 levels are increased by interferon gamma in breast cancer cells. Biochem Biophys Res Commun 2018; 499:973-978. [DOI: 10.1016/j.bbrc.2018.04.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 04/03/2018] [Indexed: 11/24/2022]
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One-Step 18F-Labeling of Estradiol Derivative for PET Imaging of Breast Cancer. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:5362329. [PMID: 29692688 PMCID: PMC5859795 DOI: 10.1155/2018/5362329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 01/17/2018] [Indexed: 01/17/2023]
Abstract
Positron emission tomography (PET) imaging is a useful method to evaluate in situ estrogen receptor (ER) status for the early diagnosis of breast cancer and optimization of the appropriate treatment strategy. The 18F-labeled estradiol derivative has been successfully used to clinically assess the ER level of breast cancer. In order to simplify the radiosynthesis process, one-step 18F-19F isotope exchange reaction was employed for the 18F-fluorination of the tracer of [18F]AmBF3-TEG-ES. The radiotracer was obtained with the radiochemical yield (RCY) of ~61% and the radiochemical purity (RCP) of >98% within 40 min. Cell uptake and blocking assays indicated that the tracer could selectively accumulate in the ER-positive human breast cancer cell lines MCF-7 and T47D. In vivo PET imaging on the MCF-7 tumor-bearing mice showed relatively high tumor uptake (1.4~2.3 %D/g) and tumor/muscle uptake ratio (4~6). These results indicated that the tracer is a promising PET imaging agent for ER-positive breast cancers.
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Tecalco-Cruz AC. Molecular pathways involved in the transport of nuclear receptors from the nucleus to cytoplasm. J Steroid Biochem Mol Biol 2018; 178:36-44. [PMID: 29107180 DOI: 10.1016/j.jsbmb.2017.10.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/18/2017] [Accepted: 10/25/2017] [Indexed: 12/30/2022]
Abstract
Nuclear receptors (NRs) are transcription regulators that direct the expression of many genes linked to cellular processes, such as proliferation, differentiation, and apoptosis. Additionally, some cellular events are also modulated by signaling pathways induced by NRs outside of the nucleus. Hence, the subcellular transport of NRs is dynamic and is modulated by several signals, protein-protein interactions, and posttranslational modifications. Particularly, the exit of NRs from the nucleus to cytoplasm and/or other compartments is transcendental, as it is this export event, which determines their abundance in the cells' compartments, the activation or attenuation of nuclear or extranuclear pathways, and the magnitude and duration of their effects inside or outside of the nucleus. Consequently, an adequate control of the distribution of NRs is critical for homeostasis, because a deregulation in the nucleo-cytoplasmic transport of NRs could be involved in diseases including cancer as well as metabolic and vascular alterations. In this review, we investigated the pathways and molecular and biological aspects that have been described for the nuclear export of NRs so far and their functional relevance in some diseases. This information suggests that the transport of NRs out of the nucleus is a key mechanism for the identification of new therapeutic targets for alterations associated with the deregulation of the function of NRs.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apdo Postal, D.F. 04510, Mexico.
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Vaklavas C, Zinn KR, Samuel SL, Meng Z, Grizzle WE, Choi H, Blume SW. Translational control of the undifferentiated phenotype in ER‑positive breast tumor cells: Cytoplasmic localization of ERα and impact of IRES inhibition. Oncol Rep 2018; 39:2482-2498. [PMID: 29620220 PMCID: PMC5983923 DOI: 10.3892/or.2018.6332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/12/2018] [Indexed: 01/07/2023] Open
Abstract
Using a series of potential biomarkers relevant to mechanisms of protein synthesis, we observed that estrogen receptor (ER)-positive breast tumor cells exist in two distinct yet interconvertible phenotypic states (of roughly equal proportion) which differ in the degree of differentiation and use of IRES-mediated translation. Nascently translated IGF1R in the cytoplasm positively correlated with IRES activity and the undifferentiated phenotype, while epitope accessibility of RACK1, an integral component of the 40S ribosomal subunit, aligned with the more differentiated IRES-off state. When deprived of soluble growth factors, the entire tumor cell population shifted to the undifferentiated phenotype in which IRES-mediated translation was active, facilitating survival under these adverse microenvironmental conditions. However, if IRES-mediated translation was inhibited, the cells instead were forced to transition uniformly to the more differentiated state. Notably, cytoplasmic localization of estrogen receptor α (ERα/ESR1) precisely mirrored the pattern observed with nascent IGF1R, correlating with the undifferentiated IRES-active phenotype. Inhibition of IRES-mediated translation resulted in both a shift in ERα to the nucleus (consistent with differentiation) and a marked decrease in ERα abundance (consistent with the inhibition of ERα synthesis via its IRES). Although breast tumor cells tolerated forced differentiation without extensive loss of their viability, their reproductive capacity was severely compromised. In addition, CDK1 was decreased, connexin 43 eliminated and Myc translation altered as a consequence of IRES inhibition. Isolated or low-density ER-positive breast tumor cells were particularly vulnerable to IRES inhibition, losing the ability to generate viable cohesive colonies, or undergoing massive cell death. Collectively, these results provide further evidence for the integral relationship between IRES-mediated translation and the undifferentiated phenotype and demonstrate how therapeutic manipulation of this specialized mode of protein synthesis may be used to limit the phenotypic plasticity and incapacitate or eliminate these otherwise highly resilient breast tumor cells.
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Affiliation(s)
- Christos Vaklavas
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kurt R Zinn
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Sharon L Samuel
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Zheng Meng
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - William E Grizzle
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Hyoungsoo Choi
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Scott W Blume
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Natural Anti-Estrogen Receptor Alpha Antibodies Able to Induce Estrogenic Responses in Breast Cancer Cells: Hypotheses Concerning Their Mechanisms of Action and Emergence. Int J Mol Sci 2018; 19:ijms19020411. [PMID: 29385743 PMCID: PMC5855633 DOI: 10.3390/ijms19020411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 01/24/2018] [Accepted: 01/25/2018] [Indexed: 02/04/2023] Open
Abstract
The detection of human anti-estrogen receptor α antibodies (ERαABs) inducing estrogenic responses in MCF-7 mammary tumor cells suggests their implication in breast cancer emergence and/or evolution. A recent report revealing a correlation between the titer of such antibodies in sera from patients suffering from this disease and the percentage of proliferative cells in samples taken from their tumors supports this concept. Complementary evidence of the ability of ERαABs to interact with an epitope localized within the estradiol-binding core of ERα also argues in its favor. This epitope is indeed inserted in a regulatory platform implicated in ERα-initiated signal transduction pathways and transcriptions. According to some experimental observations, two auto-immune reactions may already be advocated to explain the emergence of ERαABs: one involving probably the idiotypic network to produce antibodies acting as estrogenic secretions and the other based on antibodies able to abrogate the action of a natural ERα inhibitor or to prevent the competitive inhibitory potency of released receptor degradation products able to entrap circulating estrogens and co-activators. All of this information, the aspect of which is mainly fundamental, may open new ways in the current tendency to combine immunological and endocrine approaches for the management of breast cancer.
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Rajagopal C, Lankadasari MB, Aranjani JM, Harikumar KB. Targeting oncogenic transcription factors by polyphenols: A novel approach for cancer therapy. Pharmacol Res 2018; 130:273-291. [PMID: 29305909 DOI: 10.1016/j.phrs.2017.12.034] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 11/30/2017] [Accepted: 12/31/2017] [Indexed: 02/06/2023]
Abstract
Inflammation is one of the major causative factor of cancer and chronic inflammation is involved in all the major steps of cancer initiation, progression metastasis and drug resistance. The molecular mechanism of inflammation driven cancer is the complex interplay between oncogenic and tumor suppressive transcription factors which include FOXM1, NF-kB, STAT3, Wnt/β- Catenin, HIF-1α, NRF2, androgen and estrogen receptors. Several products derived from natural sources modulate the expression and activity of multiple transcription factors in various tumor models as evident from studies conducted in cell lines, pre-clinical models and clinical samples. Further combination of these natural products along with currently approved cancer therapies added an additional advantage and they considered as promising targets for prevention and treatment of inflammation and cancer. In this review we discuss the application of multi-targeting natural products by analyzing the literature and future directions for their plausible applications in drug discovery.
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Affiliation(s)
- Chitra Rajagopal
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
| | - Manendra Babu Lankadasari
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
| | - Jesil Mathew Aranjani
- Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - K B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India.
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Li M, Zhang C, Zhong Y, Zhao J. Cellular localization of ATBF1 protein and its functional implication in breast epithelial cells. Biochem Biophys Res Commun 2017. [DOI: 10.1016/j.bbrc.2017.06.068] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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