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Estrogen receptor (ER) mutations are common in primary endometrial cancer. However, ER mutant-driven oncogenic mechanisms in endometrial cancer are poorly understood. In their study, Blanchard and colleagues inserted common endometrial cancer mutations ER-Y537S and ER-D538G into endometrial cancer cell lines using CRISPR/Cas9 and assessed their mechanistic and phenotypic effects. RNA-Seq analysis revealed mutant-specific transcriptional programs. Correspondingly, ChIP-Seq analysis identified unique ER-Y537S and ER-D538G genomic binding sites, and ATAC-Seq analysis showed that the mutants alter chromatin accessibility in distinct loci. Both mutants enhanced endometrial cancer cell proliferation in vivo, and ER-Y537S enhanced tumor growth and metastasis in a mouse model as well. To discover potentially targetable ER cofactors in endometrial cancer, the authors performed rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME) in wild-type and mutant ER-expressing endometrial cancer cells. The authors identified cyclin dependent kinase 9 (CDK9) as an ER cofactor in endometrial cancer and demonstrated that pharmacologic...