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Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers.
Cotul, Eylem Kulkoyluoglu; Zuo, Qianying; Santaliz-Casiano, Ashlie; Imir, Ozan Berk; Mogol, Ayca Nazli; Tunc, Elif; Duong, Kevin; Lee, Jenna Kathryn; Ramesh, Rithva; Odukoya, Elijah; Kesavadas, Mrinali P; Ziogaite, Monika; Smith, Brandi Patrice; Mao, Chengjian; Shapiro, David J; Park, Ben Ho; Katzenellenbogen, Benita S; Daly, Drew; Aranda, Evelyn; O'Neill, John D; Walker, Christopher; Landesman, Yosef; Madak-Erdogan, Zeynep.
Afiliación
  • Cotul EK; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Zuo Q; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Santaliz-Casiano A; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Imir OB; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Mogol AN; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Tunc E; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Duong K; Department of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Lee JK; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Ramesh R; Department of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Odukoya E; Department of Human Development and Family Studies, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Kesavadas MP; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Ziogaite M; Department of Interdisciplinary Health Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Smith BP; Department of Informatics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Mao C; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Shapiro DJ; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Park BH; Cancer Center at Illinois, Urbana, IL 61801, USA.
  • Katzenellenbogen BS; Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Daly D; Cancer Center at Illinois, Urbana, IL 61801, USA.
  • Aranda E; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • O'Neill JD; Xylyx Bio, Inc., Brooklyn, NY 11226, USA.
  • Walker C; Xylyx Bio, Inc., Brooklyn, NY 11226, USA.
  • Landesman Y; Xylyx Bio, Inc., Brooklyn, NY 11226, USA.
  • Madak-Erdogan Z; Karyopharm Therapeutics, Newton, MA 02459, USA.
Cancers (Basel) ; 12(9)2020 Aug 24.
Article en En | MEDLINE | ID: mdl-32847042
ABSTRACT
The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. 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+. PGC1α, 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 ERα-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Cancers (Basel) Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Cancers (Basel) Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos