BRCA1 regulation on beta-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer

Human chorionic gonadotropin beta (beta-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of beta-hCG in breast cancer. We identified for the first time that beta-hCG expression is linked to BRCA1 status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and beta-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress the expression of beta-hCG by binding to its promoter. Further, beta-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of beta-hCG in BRCA1 mutant but not wild-type breast cancer cells results in the formation of spheres even on monolayer cultures. The cells of these spheres show high expression of both EMT and stem cell markers. Since beta-hCG belongs to a cysteine knot family of proteins like TGF beta and TGF beta signaling is deregulated in BRCA1 defective tumors, we checked whether beta-hCG can mediate signaling through TGF beta RII in BRCA1 mutated cells. We found for the first time that beta-hCG can bind and phosphorylate TGF beta RII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on beta-hCG and BRCA1 mutation promotes beta-hCG mediated tumorigenesis through TGF beta RII signaling. Thus inhibiting beta-hCG-TGF beta RII could prove an effective treatment strategy for BRCA1 mutated tumors.

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