No abstract

Summary Progesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α (ERα)-positive luminal breast cancers. Conversely, AR signaling may promote growth of a subset of ERα-negative, AR-positive breast cancers with a molecular apocrine phenotype. Understanding the molecular mechanisms whereby androgens can elicit distinct gene expression programs and opposing proliferative responses in these two breast cancer phenotypes is critical to the development of new therapeutic strategies to target the AR in breast cancer.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network between transcription factors (TFs) and putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via eQTLs. We identified 36 overlapping regulons that were enriched and formed a distinct cluster within the network, suggesting shared biology. The risk-TFs driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to ER+ luminal A/B and to ER− basal-like cancers and to different, luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation to reveal the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.

No abstract

Oocytes regulate follicle growth by secreting paracrine growth factors that act on neighbouring granulosa cells (GCs). Those factors identified to date are mainly members of the transforming growth factor-␤ ␤ (TGF␤ ␤) superfamily, but little is known about which specific receptor/signalling system(s) they employ. This study was conducted to determine the requisite pathways utilised by oocytes to promote GC proliferation. We used an established oocytesecreted mitogen bioassay, where denuded mouse oocytes are co-cultured with mural GCs. Oocytes, growth differentiation factor-9 (GDF9), TGF␤ ␤1 and activin-A all promoted GC DNA synthesis, but bone-morphogenetic protein 6 (BMP6) did not. Subsequently, we tested the capacity of various TGF␤ ␤ superfamily receptor ectodomains (ECD) to neutralise oocyte-or specific growth factor-stimulated GC proliferation. The BMP type-II receptor (BMPR-II) ECD antagonised oocyte and GDF9 bioactivity dose-dependently, but had no or minimal effect on TGF␤ ␤1 and activin-A bioactivity, demonstrating its specificity. The TGF␤ ␤R-II, activinR-IIA and activinR-IIB ECDs all failed to neutralise oocyte-or GDF9-stimulated GC DNA synthesis, whereas they did antagonise the activity of their respective native ligands. An activin receptor-like kinase (ALK) 4/5/7 inhibitor, SB431542, also antagonised both oocyte and GDF9 bioactivity in a dosedependent manner. Consistent with these findings, oocytes, GDF9 and TGF␤ ␤1 all activated SMAD2/3 reporter constructs in transfected GC, and led to phosphorylation of SMAD2 proteins in treated cells. Surprisingly, oocytes did not activate the SMAD1/5/8 pathway in transfected GCs although exogenous BMP6 did. This study indicates that oocyte paracrine factors primarily utilise a similar signalling pathway first identified for GDF9 that employs an unusual combination of TGF␤ ␤ superfamily receptors, the BMPR-II and a SMAD2/3 stimulatory ALK (4, 5 or 7), for transmitting their mitogenic actions in GC. This cellsignalling pathway may also have relevance in the hypothalamic-pituitary axis and in germ-somatic cell interactions in the testis.

No abstract

Individual and concerted actions of ER and PR highlight the prognostic and therapeutic value of PR in ER+/PR+ breast cancers.