PLX116690

GSE99680: Estrogen signaling is functionally reprogrammed in breast tumorigenesis

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Background: The estrogen receptor (ER) is expressed in approximately 70% of sporadic breast cancers and is known to activate genes driving cell proliferation. Much work in the field has characterized the mechanisms of ER-signaling behind cancer progression and eventual metastasis, and therapeutic targeting of the ER signaling pathway has proven effective. However, little is known regarding the role of ER in the initial process of transformation. Since ER possesses pro-differentiation roles in normal breast development yet becomes one of the drivers of breast cancer, altered ER function is then likely a crucial first step. We seek to investigate the role of ER from the perspective of the normal breast to allow for mechanistic insights into breast tumorigenesis.; Results: Gene expression profiling via RNA-seq of breast epithelial cells from seven reduction mammoplasties reveal a drastically different and muted normal response to estrogen stimulation. Genes that promote cell cycling and cell proliferation were downregulated in normal breast but were upregulated in breast cancer cells. Furthermore, differential ER binding alone via ER ChIP-seq is capable of segregating ten primary breast tumors from seven normal breast tissues with very few overlapping sites. Deeper motif analysis reveals the enrichment of novel transcription cofactor GRHL2 in the binding sites most closely associated to ER+ breast cancer. Further findings via genome-wide CRISPR screens reveal GRHL2 as an essential gene in luminal ER+ breast cancer with predictive ability in cancer risk and prognosis.; Conclusions: Cellular reprogramming of the ER signaling network may alter the functioning phenotype of normal mammary epithelial cells and offer mechanistic insights into the series of events for breast tumorigenesis. Notably, ER activation does not promote cellular proliferation in normal mammary epithelial cells, and the interaction with transcriptional cofactors such as GRHL2 can be a driving mechanism for breast tumorigenesis. Unraveling the differential ER signaling normal mammary epithelium and breast cancer will enhance our understanding of breast tumorigenesis and aid the development of more effective prevention strategies and targeted therapeutics. SOURCE: Hari Singhal (hari_singhal@dfci.harvard.edu) - Geoffrey L Greene University of Chicago