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Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance
A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to eluci...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520695/ https://www.ncbi.nlm.nih.gov/pubmed/30987380 http://dx.doi.org/10.3390/cancers11040479 |
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author | Kulkoyluoglu-Cotul, Eylem Smith, Brandi Patrice Wrobel, Kinga Chen Zhao, Yiru Chen, Karen Lee Ann Hieronymi, Kadriye Imir, Ozan Berk Duong, Kevin O’Callaghan, Caitlin Mehta, Aditi Sahoo, Sunati Haley, Barbara Chang, Hua Landesman, Yosef Madak-Erdogan, Zeynep |
author_facet | Kulkoyluoglu-Cotul, Eylem Smith, Brandi Patrice Wrobel, Kinga Chen Zhao, Yiru Chen, Karen Lee Ann Hieronymi, Kadriye Imir, Ozan Berk Duong, Kevin O’Callaghan, Caitlin Mehta, Aditi Sahoo, Sunati Haley, Barbara Chang, Hua Landesman, Yosef Madak-Erdogan, Zeynep |
author_sort | Kulkoyluoglu-Cotul, Eylem |
collection | PubMed |
description | A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and/or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. |
format | Online Article Text |
id | pubmed-6520695 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-65206952019-05-31 Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance Kulkoyluoglu-Cotul, Eylem Smith, Brandi Patrice Wrobel, Kinga Chen Zhao, Yiru Chen, Karen Lee Ann Hieronymi, Kadriye Imir, Ozan Berk Duong, Kevin O’Callaghan, Caitlin Mehta, Aditi Sahoo, Sunati Haley, Barbara Chang, Hua Landesman, Yosef Madak-Erdogan, Zeynep Cancers (Basel) Article A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and/or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. MDPI 2019-04-04 /pmc/articles/PMC6520695/ /pubmed/30987380 http://dx.doi.org/10.3390/cancers11040479 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kulkoyluoglu-Cotul, Eylem Smith, Brandi Patrice Wrobel, Kinga Chen Zhao, Yiru Chen, Karen Lee Ann Hieronymi, Kadriye Imir, Ozan Berk Duong, Kevin O’Callaghan, Caitlin Mehta, Aditi Sahoo, Sunati Haley, Barbara Chang, Hua Landesman, Yosef Madak-Erdogan, Zeynep Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance |
title | Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance |
title_full | Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance |
title_fullStr | Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance |
title_full_unstemmed | Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance |
title_short | Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance |
title_sort | combined targeting of estrogen receptor alpha and xpo1 prevent akt activation, remodel metabolic pathways and induce autophagy to overcome tamoxifen resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520695/ https://www.ncbi.nlm.nih.gov/pubmed/30987380 http://dx.doi.org/10.3390/cancers11040479 |
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