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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

1
Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
2
Illinois Informatics Institute, University of Illinois, Urbana-Champaign, Champaign, IL 61820, USA
3
Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
4
School of Molecular and Cellular Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
5
Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
6
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
7
UTSW Medical Center, Dallas, TX 75390, USA
8
Karyopharm Therapeutics, Newton, MA 02459, USA
9
National Center for Supercomputing Applications, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
10
Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(4), 479; https://doi.org/10.3390/cancers11040479
Received: 27 February 2019 / Revised: 29 March 2019 / Accepted: 29 March 2019 / Published: 4 April 2019
(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)
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PDF [4168 KB, uploaded 19 April 2019]
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Abstract

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. View Full-Text
Keywords: breast cancer; endocrine resistance; nuclear transport pathways; XPO1; ERα; metabolic rewiring breast cancer; endocrine resistance; nuclear transport pathways; XPO1; ERα; metabolic rewiring
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Kulkoyluoglu-Cotul, E.; Smith, B.P.; Wrobel, K.; Chen Zhao, Y.; Chen, K.L.A.; Hieronymi, K.; Imir, O.B.; Duong, K.; O’Callaghan, C.; Mehta, A.; Sahoo, S.; Haley, B.; Chang, H.; Landesman, Y.; Madak-Erdogan, Z. Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance. Cancers 2019, 11, 479.

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