雌激素受体α
生物
癌症研究
雌激素受体
子宫内膜癌
突变体
染色质免疫沉淀
表型
突变
等位基因
基因
癌症
遗传学
乳腺癌
基因表达
发起人
作者
Zannel Blanchard,Spencer Arnesen,Jeffery M. Vahrenkamp,Adriana Pinheiro Martinelli Rodriguez,Elke A. Jarboe,Callie L. Brown,Katarzyna Modzelewska,David H. Lum,Jason Gertz
标识
DOI:10.1101/2022.06.13.495977
摘要
Activating estrogen receptor alpha (ER) 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 to 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 (RIME) 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.
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