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

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.

Vasculogenic Mimicry in Breast Cancer: Clinical Relevance and Drivers

“…On the other hand, an inverse correlation between BRCA1 and hCG has been found. Indeed, BRCA1 directly represses the expression of β-hCG by binding to its promoter [ 60 ]. This hormone is known to exert a potent proangiogenic effect on hCG/luteinizing hormone receptor (hCG/LH-R)-expressing uterine ECs.…”

“…Interestingly, mutated BRCA1 in breast cancer cells is associated with β-hCG overexpression, which results in pluripotency and EMT. Besides, this correlated with enhanced migration, invasion, and greater tumorigenic capacity along with expression of EMT and stem cell markers [ 60 ]. Notably, all the cellular processes aberrantly activated in BRCA1-mutated cancers are closely related to the VM capacity of tumors, and it has been documented that hCG is crucial for the transdifferentiation of cancer cells into endothelial-like cells by inducing expression of ECs markers such as CD31 and VEGF among others [ 62 ].…”

“…Notably, all the cellular processes aberrantly activated in BRCA1-mutated cancers are closely related to the VM capacity of tumors, and it has been documented that hCG is crucial for the transdifferentiation of cancer cells into endothelial-like cells by inducing expression of ECs markers such as CD31 and VEGF among others [ 62 ]. Remarkably, in breast cancer with mutated BRCA1, β-hCG can signal through transforming growth factor beta receptor II (TGFβRII) regardless of the hCG/LH-R status, resulting in increased cell proliferation [ 60 ]. The activation of the TGFB signaling pathway also induces the expression of Snail, Slug, TWIST, and ZEB-1, which in turn increase the expression of mesenchymal markers leading to EMT, a well-known driver of VM.…”

“…Another strategy to take into account is the targeting of β-hCG, due to its immune suppressor functions and its vasculogenic effects on BRCA1 defective tumors; however, as mentioned above, this is highly dependent on the molecular characteristics of patients [ 60 ], warranting further studies.…”

Unconventional Actions of Glycoprotein Hormone Subunits: A Comprehensive Review

“…Pro-metastatic roles were also attributed to β-hCG in several other cancer cell lines ( 172 – 174 ). BRCA1 (for Breast Cancer 1) was shown to down regulate β-hCG expression in breast cancer cells so that cancer cells harboring inactivating mutation in BRCA1 have high level of β-hCG ( 175 ). In agreement with a role of β-hCG in promoting metastasis, knockdown of β-hCG in BRCA1 mutant HCC1937 cells by siRNA significantly reduced their migration and invasion capacities ( 175 ).…”