TY - JOUR
T1 - Allele-Specific Gene Regulation, Phenotypes, and Therapeutic Vulnerabilities in Estrogen Receptor Alpha-Mutant Endometrial Cancer
AU - Blanchard, Zannel
AU - Rush, Craig M.
AU - Arnesen, Spencer
AU - Vahrenkamp, Jeffery M.
AU - Rodriguez, Adriana C.
AU - Jarboe, Elke A.
AU - Brown, Callie
AU - Chang, Matthew E.K.
AU - Flory, Mark R.
AU - Mohammed, Hisham
AU - Modzelewska, Katarzyna
AU - Lum, David H.
AU - Gertz, Jason
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Activating estrogen receptor alpha (ER; also known as ESR1) mutations are present in primary endometrial and metastatic breast cancers, promoting estrogen-independent activation of the receptor. Functional characterizations in breast cancer have established unique molecular and phenotypic consequences of the receptor, yet the impact of ER mutations in endometrial cancer has not been fully explored. In this study, we used CRISPR-Cas9 to model the clinically prevalent ER-Y537S mutation and compared results with ER-D538G to discover allele-specific differences between ER mutations in endometrial cancer. We found that constitutive activity of mutant ER resulted in changes in the expression of thousands of genes, stemming from combined alterations to ER binding and chromatin accessibility. The unique gene expression programs resulted in ER-mutant cells developing increased cancer-associated phenotypes, including migration, invasion, anchorage-independent growth, and growth in vivo. To uncover potential treatment strategies, we identified ER-associated proteins via Rapid Immunoprecipitation and Mass Spectrometry of Endogenous Proteins and interrogated two candidates, CDK9 and NCOA3. Inhibition of these regulatory proteins resulted in decreased growth and migration, representing potential novel treatment strategies for ER-mutant endometrial cancer. Implications: This study provides insight into mutant ER activity in endometrial cancer and identifies potential therapies for women with ER-mutant endometrial cancer.
AB - Activating estrogen receptor alpha (ER; also known as ESR1) mutations are present in primary endometrial and metastatic breast cancers, promoting estrogen-independent activation of the receptor. Functional characterizations in breast cancer have established unique molecular and phenotypic consequences of the receptor, yet the impact of ER mutations in endometrial cancer has not been fully explored. In this study, we used CRISPR-Cas9 to model the clinically prevalent ER-Y537S mutation and compared results with ER-D538G to discover allele-specific differences between ER mutations in endometrial cancer. We found that constitutive activity of mutant ER resulted in changes in the expression of thousands of genes, stemming from combined alterations to ER binding and chromatin accessibility. The unique gene expression programs resulted in ER-mutant cells developing increased cancer-associated phenotypes, including migration, invasion, anchorage-independent growth, and growth in vivo. To uncover potential treatment strategies, we identified ER-associated proteins via Rapid Immunoprecipitation and Mass Spectrometry of Endogenous Proteins and interrogated two candidates, CDK9 and NCOA3. Inhibition of these regulatory proteins resulted in decreased growth and migration, representing potential novel treatment strategies for ER-mutant endometrial cancer. Implications: This study provides insight into mutant ER activity in endometrial cancer and identifies potential therapies for women with ER-mutant endometrial cancer.
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U2 - 10.1158/1541-7786.MCR-22-0848
DO - 10.1158/1541-7786.MCR-22-0848
M3 - Article
C2 - 37363949
AN - SCOPUS:85174641944
SN - 1541-7786
VL - 21
SP - 1023
EP - 1036
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 10
ER -