An epigenomic approach to therapy for tamoxifen-resistant breast cancer
| العنوان: | An epigenomic approach to therapy for tamoxifen-resistant breast cancer |
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| المؤلفون: | Nicholas Mitsiades, Rainer B. Lanz, Cristian Coarfa, Chad J. Creighton, Zheng Zhang, Yongcheng Song, Xiaoyong Fu, Bert W. O'Malley, C. Kent Osborne, Qin Feng, Constantine S. Mitsiades, Bin He, Agostina Nardone, James E. Bradner, Martin Shea, Rachel Schiff, Lei Wang, Susan G. Hilsenbeck |
| المصدر: | Cell Research |
| بيانات النشر: | Springer Science and Business Media LLC, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Epigenomics, Estrogen receptor, Breast Neoplasms, Cell Cycle Proteins, Biology, epigenomic, Mice, breast cancer, Breast cancer, Cell Line, Tumor, medicine, Animals, Humans, skin and connective tissue diseases, Fulvestrant, Molecular Biology, Transcription factor, tamoxifen, Estradiol, Estrogen Receptor alpha, Nuclear Proteins, RNA-Binding Proteins, Cancer, Azepines, Histone-Lysine N-Methyltransferase, Cell Biology, Triazoles, medicine.disease, 3. Good health, Repressor Proteins, Drug Resistance, Neoplasm, Cancer research, Original Article, Female, Signal transduction, Estrogen receptor alpha, Tamoxifen, Signal Transduction, Transcription Factors, medicine.drug |
| الوصف: | Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer. |
| تدمد: | 1748-7838 1001-0602 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::40c16f2d3cdf58d637fb10ef1da2be07Test https://doi.org/10.1038/cr.2014.71Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....40c16f2d3cdf58d637fb10ef1da2be07 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17487838 10010602 |
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