BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

Abstract

Follistatin (FST), a folliculogenesis regulating protein, is found in relatively high concentrations in female ovarian tissues. FST acts as an antagonist to Activin, which is often elevated in human ovarian carcinoma, and thus may serve as a potential target for therapeutic intervention against ovarian cancer. The breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor gene in human breast cancer; however its role in ovarian cancer is not well understood. We performed microarray analysis on human ovarian carcinoma cell line SKOV3 that stably overexpress wild-type BRCA1 and compared with the corresponding empty vector-transfected clones. We found that stable expression of BRCA1 not only stimulates FST secretion but also simultaneously inhibits Activin expression. To determine the physiological importance of this phenomenon, we further investigated the effect of cellular BRCA1 on the FST secretion in immortalized ovarian surface epithelial (IOSE) cells derived from either normal human ovaries or ovaries of an ovarian cancer patient carrying a mutation in BRCA1 gene. Knock-down of BRCA1 in normal IOSE cells demonstrates down-regulation of FST secretion along with the simultaneous up-regulation of Activin expression. Furthermore, knock-down of FST in IOSE cell lines as well as SKOV3 cell line showed significantly reduced cell proliferation and decreased cell migration when compared with the respective controls. Thus, these findings suggest a novel function for BRCA1 as a regulator of FST expression and function in human ovarian cells.

STAT3 Inhibits Cell Proliferation at Least in Part Via Directly Negatively Regulating FST Gene Expression

“…In agreement with our results, it has been shown that FST promotes the proliferation of duck primary myoblasts [45]. The knock-down of FST significantly reduced the proliferation of the immortalized ovarian surface epithelial and human ovarian carcinoma cell line SKOV3 [46]. Previous studies showed STAT3 overexpression inhibited the proliferation of mouse leukocyte and hepatocyte via inhibiting cyclin D expression [38,39], as well as chondrogenic cell line ATDC5 [40].…”

First-in-Human Phase I Study of the Activin A Inhibitor, STM 434, in Patients with Granulosa Cell Ovarian Cancer and Other Advanced Solid Tumors

“…Additional data suggest that mutations more commonly associated with distinct ovarian cancer histologies including BRCA1 (serous), ARID1A (endometriosis associated clear cell and endometrioid), and FOXL2 (granulosa cell) may promote dysregulation in activin signaling and may further enhance dependence on this pathway (16,17). For example, downregulation of BRCA1 indirectly enhances activin signaling through downregulation of the activin antagonist follistatin alongside upregulation of ActR2B, with the net effect of establishing an autocrine loop feeding cell proliferation (16). Moreover, the tumor suppressor activity of ARID1A is mediated through SMAD3, a key transducer of activin signaling (17,18).…”

Multi-omics analysis of the Indian ovarian cancer cohort revealed histotype-specific mutation and gene expression patterns

“…Whereas, Granulosa cell tumours showed enrichment of antagonism of Activin and Follistatin in the Indian Cohort. Follistatin antagonises activin, which is overexpressed in OVCa, with its levels in turn regulated by BRCA1 ( Karve et al, 2012 ). Activin inhibitor STM 434 is in Phase I clinical trial for granulosa cell tumour ( Tao et al, 2019 ).…”