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The Grainyhead-like protein family, composed of GRHL1, GRHL2, and GRHL3, are nuclear transcription factors that regulate epithelial differentiation. GRHL2 has been associated with several nuclear hormone receptors, including progesterone receptor (PR), androgen receptor (AR), and more recently, estrogen receptor (ER). In breast cancer, GRHL2 has been shown to both activate ER-dependent enhancers through FOXA1 and MLL3-mediated deposition of the activating histone mark H3K4me1 and repress enhancers via inhibition of the histone acetyltransferase p300. Cistromic analysis by our group of ER phosphorylated at serine 118 (pS118-ER), a form of transcriptionally active ER, found an enrichment of the GRHL motif near pS118-ER binding sites. Despite these findings, the direct relationship between GRHL2 and ER transcriptional function and how that relationship influences ER-positive breast cancer growth and differentiation is not well-defined. To explore the relationship between GRHL2 and pS118-ER further, we used transcriptomic and cistromic analysis of ER-positive cells lacking GRHL2 to determine the impact of the loss of GRHL2 on cellular and transcriptional responses to estrogen. This analysis identified a subset of genes that are controlled by both GRHL2 and estrogen. In addition, CRISPR engineered T47D cells lacking a portion of the GRHL2 transactivation domain (ΔTAD) demonstrate reduced nuclear ER levels and reduced ER chromatin occupancy. Gene expression analysis of ΔTAD-GRHL2 cells showed increased GRHL3 expression, and ChIP analysis revealed increased Pol II occupancy at the GRHL3 promoter, suggesting that there may be a compensatory mechanism within the GRHL family to regulate the transcriptome. Finally, ΔTAD-GRHL2 mutants reduced growth and colony formation relative to wild-type controls. Together, this work will provide an understanding of how transcriptionally active ER and GRHL2 selectively cooperate to regulate transcription, growth, and differentiation in ER-positive breast cancer.

The Transcriptional Function of GRHL2 in Hormone-Dependent Breast Cancers