Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance
| العنوان: | Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance |
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| المؤلفون: | Sabino De Placido, Powel H. Brown, Carmine De Angelis, Mario Giuliano, Ilenia Migliaccio, N.A. Healy, C. Kent Osborne, Suleiman Massarweh, Rinath Jeselsohn, Rachel Schiff, Xiaoyong Fu, Carolina Gutierrez, Myles Brown, Susan G. Hilsenbeck, Meghana V. Trivedi, Chad J. Creighton, Tao Wang, Abhijit Mazumdar, Mathieu Lupien, Luca Malorni |
| المساهمون: | Malorni, Luca, Giuliano, Mario, Migliaccio, Ilenia, Wang, Tao, Creighton, Chad J., Lupien, Mathieu, Fu, Xiaoyong, Hilsenbeck, Susan G., Healy, Nuala, DE ANGELIS, Carmine, Mazumdar, Abhijit, Trivedi, Meghana V., Massarweh, Suleiman, Gutierrez, Carolina, DE PLACIDO, Sabino, Jeselsohn, Rinath, Brown, Myle, Brown, Powel H., Kent Osborne, C., Schiff, Rachel |
| المصدر: | Molecular cancer research : MCR, vol 14, iss 5 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Drug Resistance, Estrogen receptor, Mice, 0302 clinical medicine, Receptors, 2.1 Biological and endogenous factors, Aetiology, Promoter Regions, Genetic, Receptor, Cancer, Estradiol, Kinase, Drug Synergism, Receptors, Estrogen, Oncology, Cistrome, 030220 oncology & carcinogenesis, MCF-7 Cells, Female, medicine.drug, Oncology and Carcinogenesis, Breast Neoplasms, Biology, Article, Promoter Regions, 03 medical and health sciences, Genetic, Breast Cancer, Genetics, medicine, Animals, Humans, Endocrine system, Oncology & Carcinogenesis, Molecular Biology, Transcription factor, Cell Proliferation, medicine.disease, Estrogen, Xenograft Model Antitumor Assays, Transcription Factor AP-1, Tamoxifen, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, Neoplasm, Developmental Biology |
| الوصف: | The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo . AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro , accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo , promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program. Implications: AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470–81. ©2016 AACR . This article is featured in Highlights of This Issue, [p. 409][1] [1]: /lookup/volpage/14/409?iss=5 |
| وصف الملف: | application/pdf |
| تدمد: | 1557-3125 1541-7786 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2a23f0374fb0ecd4ea52cee1eb879b96Test https://doi.org/10.1158/1541-7786.mcr-15-0423Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2a23f0374fb0ecd4ea52cee1eb879b96 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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