BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates whereas the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.
Background Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, while the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Methods Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the NCI-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this pre-planned analysis. Due to the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points based on the 98th percentile. Results The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. Conclusions To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (~ 50 for premenopausal women, 40 for premenopausal on OC, 35 for postmenopausal women).
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