TY - JOUR
T1 - Combined targeting of estrogen receptor alpha and XPO1 prevent AKT activation, remodel metabolic pathways and induce autophagy to overcome tamoxifen resistance
AU - Kulkoyluoglu-Cotul, Eylem
AU - Smith, Brandi Patrice
AU - Wrobel, Kinga
AU - Zhao, Yiru Chen
AU - Chen, Karen Lee Ann
AU - Hieronymi, Kadriye
AU - Imir, Ozan Berk
AU - Duong, Kevin
AU - O’Callaghan, Caitlin
AU - Mehta, Aditi
AU - Sahoo, Sunati
AU - Haley, Barbara
AU - Chang, Hua
AU - Landesman, Yosef
AU - Madak-Erdogan, Zeynep
N1 - Funding Information:
Funding: This work was supported by grants from the University of Illinois, Office of the Vice Chancellor for Research, Arnold O. Beckman award RB17083 (to Z.M.-E.), Karyopharm Investigator-initiated research grant (to Z.M.-E.) and National Institute of Food and Agriculture, U.S. Department of Agriculture, award ILLU-698-909 (to Z.M.-E.). C.O. and A.M. are part of the ResearcHStart, a program of the Cancer Center at Illinois at the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign. The program is funded through philanthropic support from Ira and Debra Cohen, Kim Duchossois, and other generous donors.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/4
Y1 - 2019/4
N2 - 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 signalingand 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 TAMresistant 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.
AB - 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 signalingand 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 TAMresistant 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.
KW - Breast cancer
KW - ERα
KW - Endocrine resistance
KW - Metabolic Rewiring
KW - Nuclear transport pathways
KW - XPO1
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U2 - 10.3390/cancers11040479
DO - 10.3390/cancers11040479
M3 - Article
C2 - 30987380
AN - SCOPUS:85065316595
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 4
M1 - 479
ER -