Breast cancer development in BRCA1/2 mutation carriers is a net consequence of cell-autonomous and cell nonautonomous factors which may serve as excellent targets for cancer prevention. In light of our previous data we sought to investigate the consequences of the BRCA-mutation carrier state on RANKL/osteoprotegerin (OPG) signalling.We analysed serum levels of RANKL, OPG, RANKL/OPG complex, oestradiol (E2), and progesterone (P) during menstrual cycle progression in 391 BRCA1/2-mutation carriers and 782 noncarriers. These studies were complemented by analyses of RANKL and OPG in the serum and mammary tissues of female cynomolgus macaques (n = 88) and serum RANKL and OPG in postmenopausal women (n = 150).BRCA-mutation carriers had lower mean values of free serum OPG in particular in BRCA1-mutation carriers (p = 0.018) compared with controls. Among BRCA1/2 mutation carriers, lower OPG levels were associated with germline mutation locations known to confer an increased breast cancer risk (p = 0.003). P is associated with low OPG levels in serum and tissue, particularly in BRCA-mutation carriers (rho = − 0.216; p = 0.002). Serum OPG levels were inversely correlated (rho = − 0.545, p < 0.001) with mammary epithelial proliferation measured by Ki67 expression and increased (p = 0.01) in postmenopause.The P–RANKL/OPG system is dysregulated in BRCA-mutation carriers. These and previously published data provide a strong rationale for further investigation of antiprogestogens or an anti-RANKL antibody such as denosumab for breast cancer prevention.

serves on speakers bureaus for Gilead Sciences and Teva; S.S.M. was an employee of Gilead Sciences and is an equity holder of Gilead Sciences and Five Prime Therapeutics; P.B. is an employee of and has stock holdings in Gilead Sciences, holds a leadership role on the board of directors for Tioma Therapeutics, consults for Dicerna Pharmaceuticals, and has intellectual property interests with Sanofi and AVEO Pharmaceuticals; P.C.Y., R.H., X.H., and J.J. are employees and stockholders of Gilead Sciences; C.D.F. declares no competing financial interests. Z.Z. was an employee of Gilead Sciences.

Background To explore the development mechanism of PCOS and Transcriptomics was applied to seek the key gene. Methods Transcriptomics marked by UID (unique identifier) technique of granulosa cell in PCOS and control women was carried out and key gene was picked up. Then the key gene in granulosa cell was measured by RT-PCR. Two PCOS models modeling with Letrozole and Testosterone Propionate were implemented and the key gene in granulosa cell of ovary was measured by immunohistochemistry to verify the relation with PCOS. Results GO-enrich of transcriptomics concentrated in domain steroid metabolism and domain mitochondria. Different genes were sought from coexisting in both domain steroid metabolism and domain mitochondria. Finally, five different genes including CYP11A1、CYB5R1、STAR、FDX1 and AMACR were obtained. RT-PCR was implemented to furtherly verify the downregulating mRNA of FDX1 in PCOS, which showed the consistent outcome with the transcriptomics. Level of FDX1 protein in granulosa cell of antral follicle in two PCOS models was measured and decreased. Conclusions FDX1 was related with steroid metabolism and mitochondrial and may participate in the development of PCOS.

<p>Supplemental Figure 1. Study design</p>

<p>Supplemental Figure 3. Mean (SD) TIRA plasma concentration. Cycle 1 Day 8 data are shown in patients receiving TIRA monotherapy with A) TIRA/IDELA, and B) TIRA/ENTO*</p>