Estrogen receptor signaling is reprogrammed during breast tumorigenesis

Abstract

Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER + mature luminal mammary epithelial cells and ER + breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancerspecific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER + breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with ER + breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics.breast cancer | estrogen receptor | mammary gland | cancer genomics | tumorigenesis

FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer

“…Interestingly, one of these GO term genes that was DN upon FOXA1 OE was the gene encoding DLC1 (SI Appendix, Fig. S3C), a Rho-GAP protein that was recently reported to play an estrogen-induced tumor-suppressor role (26). This finding is also in line with the reduced classic estrogenregulated ER signaling in H-FOXA1-expressing cells, as we have previously reported (10).…”

Establishment of a Stable β-Casein Protein-Secreted Laoshan Dairy Goat Mammary Epithelial Cell Line

“…Previous studies have reported that the estrogen, progesterone, and prolactin receptors are crucial for mammary development. The prolactin receptor is especially important, as a previous study suggested that prolactin could promote mammary development via activation of the Jak2/Stat pathway ( 25 ). The ACACA and CSN2 genes are also recognized as important for controlling the contents of sheep milk.…”

MicroRNAs and Epigenetics Strategies to Reverse Breast Cancer

“…They showed that neoplastic transformation leads to transcriptional profiling shuffling upon estrogen stimulation. Interestingly, the transcriptional profile shift was primarily contributed by an active ER cistrome [174]. As the tumor progresses, cancer assumes a more aggressive phenotype like estrogen-independent cancer growth through the loss of ER expression.…”

“…The ER expression loss is more epigenetic than genetic in nature [175]. So far, reported epigenetic regulations associated with ER expression loss are (1) ER promoter hypermethylation, (2) histone deacetylation, and (3) miRNAs [174,176]. The hypermethylation of the ER gene promoter causes ER expression loss, whereas the inhibition of ER gene promoter CpG methylation reactivates the ER expression [174,177,178].…”