ERα-XPO1 Cross Talk Controls Tamoxifen Sensitivity in Tumors by Altering ERK5 Cellular Localization
| Autor: | Karen L. Chen, Sarah Li, Yiru Chen Zhao, Alexander E. Lipka, Partha S. Ray, Eylem Kulkoyluoglu, Rebecca L. Smith, Tania Ray, Jamie N. Holloway, Kadriye Hieronymi, Yosef Landesman, Zeynep Madak-Erdogan, Kinga Wrobel |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Antineoplastic Agents Hormonal Mice Nude Receptors Cytoplasmic and Nuclear Estrogen receptor Breast Neoplasms Karyopherins Biology Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Breast cancer Cell Line Tumor Gene expression medicine Animals Humans Endocrine system Receptor Molecular Biology Mitogen-Activated Protein Kinase 7 Cellular localization Original Research Cell Nucleus Regulation of gene expression Mice Inbred BALB C Estrogen Receptor alpha Biological Transport General Medicine medicine.disease Gene Expression Regulation Neoplastic Tamoxifen 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology MCF-7 Cells Cancer research Female Signal Transduction medicine.drug |
| Zdroj: | Molecular Endocrinology |
| ISSN: | 1944-9917 0888-8809 |
| Popis: | Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies. Using advanced statistical methods, we found that expression levels of several of nuclear transport genes including XPO1 were associated with poor survival and predicted recurrence of tamoxifen-treated breast tumors in human breast cancer gene expression data sets. In mechanistic studies we showed that the expression of XPO1 determined the cellular localization of the key signaling proteins and the response to tamoxifen. We demonstrated that combined targeting of XPO1 and ERα in several tamoxifen-resistant cell lines and tumor xenografts with the XPO1 inhibitor, Selinexor, and tamoxifen restored tamoxifen sensitivity and prevented recurrence in vivo. The nuclear transport pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine modulatory reagents and improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role these pathways play in reducing cancer recurrences. |
| Databáze: | OpenAIRE |
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