Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
| Autor: | Huai-Chin Chiang, Yanming Wu, Ratna K. Vadlamudi, Carmine De Angelis, Tao Hong, Xiaoyong Fu, Tim H M Huang, Rong Li, Kexin Xu, Patricia V. Elizalde, Cecilia J. Proietti, Zhao Zhang, Virginia G. Kaklamani, Mei Yang, Yiji Liao, Rachel Schiff, Mauro E. Cenciarini, Rinath Jeselsohn, Myles Brown, Matias Amasino |
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| Přispěvatelé: | Wu, Y., Zhang, Z., Cenciarini, M. E., Proietti, C. J., Amasino, M., Hong, T., Yang, M., Liao, Y., Chiang, H. -C., Kaklamani, V. G., Jeselsohn, R., Vadlamudi, R. K., Huang, T. H. -M., Li, R., De Angelis, C., Fu, X., Elizalde, P. V., Schiff, R., Brown, M., Xu, K. |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases Transcription Genetic Carcinogenesis Estrogen receptor Apoptosis medicine.disease_cause Epigenesis Genetic Mice Tumor Cells Cultured Promoter Regions Genetic Carcinogenesi DNA methylation EZH2 Estrogen Antagonists Tamoxifen resistance purl.org/becyt/ford/3.1 [https] Estrogen Antagonist Prognosis Neoplasm Proteins Gene Expression Regulation Neoplastic Oncology Histone methyltransferase purl.org/becyt/ford/3 [https] Female Breast Neoplasm medicine.drug Human Xenograft Model Antitumor Assay Prognosi Mice Nude Breast Neoplasms Biology Article Follow-Up Studie Neoplasm Protein 03 medical and health sciences medicine Biomarkers Tumor Animals Humans Enhancer of Zeste Homolog 2 Protein Cell Proliferation Epigenetic therapy Animal Estrogen Receptor alpha Apoptosi DNA Methylation Antiestrogen Xenograft Model Antitumor Assays GREB1 ERalpha signaling Tamoxifen 030104 developmental biology Drug Resistance Neoplasm Cancer research Estrogen receptor alpha Follow-Up Studies |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor a (ERa) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERa cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERa coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program. Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Fil: Wu, Yanming. University of Texas at San Antonio; Estados Unidos Fil: Zhang, Zhao. University of Texas at San Antonio; Estados Unidos Fil: Cenciarini, Mauro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Amasino, Matías Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Hong, Tao. University of Texas at San Antonio; Estados Unidos. Central South University; China Fil: Yang, Mei. University of Texas at San Antonio; Estados Unidos Fil: Liao, Yiji. University of Texas at San Antonio; Estados Unidos Fil: Chiang, Huai-Chin. University of Texas at San Antonio; Estados Unidos. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Kaklamani, Virginia G.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Jeselsohn, Rinath. Dana-farber Cancer Institute; Estados Unidos Fil: Vadlamudi, Ratna K.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Huang, Tim Hui Ming. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: Li, Rong. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; Fil: De Angelis, Carmine. Baylor College Of Medicine; Estados Unidos Fil: Fu, Xiaoyong. Baylor College Of Medicine; Estados Unidos Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Schiff, Rachel. Baylor College Of Medicine; Estados Unidos Fil: Brown, Myles. Dana farber Cancer Institute; Estados Unidos Fil: Xu, Kexin. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio |
| Databáze: | OpenAIRE |
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