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ERα-XPO1 Cross Talk Controls Tamoxifen Sensitivity in Tumors by Altering ERK5 Cellular Localization
Kinga Wrobel1, Yiru Chen Zhao1, Eylem Kulkoyluoglu1
1Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
Abstract:
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.
Insights
Targeting nuclear transport gene XPO1 with Selinexor can resensitize endocrine-resistant breast cancer (ERα(+)) to tamoxifen, offering a novel strategy to prevent recurrence and improve patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Recurrent, estrogen receptor-positive (ERα(+)), metastatic breast cancer poses a significant threat, necessitating novel therapeutic strategies.
- Endocrine therapies like tamoxifen are crucial but can fail due to acquired resistance.
- Identifying biomarkers for endocrine therapy failure and developing methods to overcome resistance are critical unmet needs.
Purpose of the Study:
- To validate nuclear transport genes, including XPO1, as biomarkers for predicting endocrine therapy failure in ERα(+) breast cancer.
- To investigate the role of XPO1 in tamoxifen resistance.
- To evaluate the efficacy of inhibiting XPO1 as a strategy to resensitize resistant tumors to endocrine therapy.
Main Methods:
- Analysis of human breast cancer gene expression data sets using advanced statistical methods to correlate nuclear transport gene expression with survival and recurrence.
- Mechanistic studies in tamoxifen-resistant cell lines and tumor xenografts to assess the impact of XPO1 expression on signaling pathways and tamoxifen response.
- In vivo evaluation of combined treatment with a XPO1 inhibitor (Selinexor) and tamoxifen.
Main Results:
- Elevated expression of nuclear transport genes, including XPO1, was associated with poor survival and predicted tamoxifen resistance in ERα(+) breast tumors.
- XPO1 expression levels influenced the cellular localization of key signaling proteins and determined the response to tamoxifen.
- Combined inhibition of XPO1 (using Selinexor) and ERα with tamoxifen restored tamoxifen sensitivity in resistant models and prevented tumor recurrence in vivo.
Conclusions:
- Nuclear transport pathways, particularly XPO1, are newly implicated in the development of endocrine resistance in ERα(+) breast cancer.
- XPO1 inhibition represents a promising therapeutic strategy to overcome tamoxifen resistance.
- These findings offer potential for improved patient selection for endocrine therapy and enhanced treatment outcomes for relapsed ERα(+) breast cancer, reducing cancer recurrence.
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