TY - JOUR
T1 - Combined targeting of estrogen receptor alpha and exportin 1 in metastatic breast cancers
AU - Cotul, Eylem Kulkoyluoglu
AU - Zuo, Qianying
AU - Santaliz-Casiano, Ashlie
AU - Imir, Ozan Berk
AU - Mogol, Ayca Nazli
AU - Tunc, Elif
AU - Duong, Kevin
AU - Lee, Jenna Kathryn
AU - Ramesh, Rithva
AU - Odukoya, Elijah
AU - Kesavadas, Mrinali P.
AU - Ziogaite, Monika
AU - Smith, Brandi Patrice
AU - Mao, Chengjian
AU - Shapiro, David J.
AU - Park, Ben Ho
AU - Katzenellenbogen, Benita S.
AU - Daly, Drew
AU - Aranda, Evelyn
AU - O’neill, John D.
AU - Walker, Christopher
AU - Landesman, Yosef
AU - Madak-Erdogan, Zeynep
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Combination therapies
KW - ESR1 mutant models
KW - Glutamine
KW - Metabolic rewiring
KW - Selinexor
KW - Tamoxifen
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U2 - 10.3390/cancers12092397
DO - 10.3390/cancers12092397
M3 - Article
C2 - 32847042
AN - SCOPUS:85090100283
SN - 2072-6694
VL - 12
SP - 1
EP - 22
JO - Cancers
JF - Cancers
IS - 9
M1 - 2397
ER -