Abstract
Human chorionic gonadotropin β (β-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 β-hCG in breast cancer. We identified for the first time that β-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 β-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 β-hCG by binding to its promoter. Further, β-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of β-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 β-hCG belongs to a cysteine knot family of proteins like TGFβ and TGFβ signaling is deregulated in BRCA1 defective tumors, we checked whether β-hCG can mediate signaling through TGFβRII in BRCA1 mutated cells. We found for the first time that β-hCG can bind and phosphorylate TGFβRII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on β-hCG and BRCA1 mutation promotes β-hCG mediated tumorigenesis through TGFβRII signaling. Thus inhibiting β-hCG-TGFβRII could prove an effective treatment strategy for BRCA1 mutated tumors.
Highlights
Human chorionic gonadotropin, a heterodimeric molecule with α and β subunits, is mainly secreted during pregnancy by the trophoblastic cells to promote implantation of the embryo
The above observations indicate that the expression of β-Human chorionic gonadotropin (hCG) might be limited to a few cancers which could be BRCA1 mutated
We report a high expression of β-subunit of hCG (β-hCG) in BRCA1 mutated breast cancer cell line which was demonstrated in vitro and in vivo
Summary
Human chorionic gonadotropin (hCG), a heterodimeric molecule with α and β subunits, is mainly secreted during pregnancy by the trophoblastic cells to promote implantation of the embryo. Many studies have revealed that the β-subunit of hCG (β-hCG). Has an independent function and is frequently associated with non-trophoblastic malignant tumors, mainly in ovarian, prostate and breast tissues.[1,2] its exact role in tumorigenesis is still unclear. Reports suggest that β-hCG can inhibit apoptosis[3] or stimulate the growth of cancer cells and that elevated serum levels of β-hCG correlate with increased aggressiveness of the cancer.[4,5] Further, it has been shown that β-hCG promotes the invasion of prostate cancer cells by activating ERK1/2 and MMP-2, as well as decreasing the expression of E-cadherin in prostate cancer cells leading to poor disease prognosis.[6,7,8] Interestingly, anti β-hCG vaccines have been developed and found to be active against β-hCG expressing cancer cells in vitro.[9,10] On the contrary, it has been found that β-hCG can induce apoptosis in breast cancer.[11,12] there exists a currently unknown variable that contextually determines the effects of β-hCG in breast cancer
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