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There is a critical need for novel therapeutic approaches to achieve tumor regression and\/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1\u03b1, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ER\u03b1-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.<\/jats:p>","DOI":"10.3390\/cancers12092397","type":"journal-article","created":{"date-parts":[[2020,8,24]],"date-time":"2020-08-24T10:37:32Z","timestamp":1598265452000},"page":"2397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-2441","authenticated-orcid":false,"given":"Eylem Kulkoyluoglu","family":"Cotul","sequence":"first","affiliation":[{"name":"Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, 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