NF-κB at the Crossroads of Normal Mammary Gland Biology and the Pathogenesis and Prevention of BRCA1-Mutated Breast Cancer

Recent studies have shown that progesterone receptor (PR)-expressing cells respond to progesterone in part through the induction of the receptor activator of NF-kappa B ligand (RANKL), which acts in a paracrine manner to induce expansion of a RANK-expressing luminal progenitor cell population. The RANK(+) population in human breast tissue from carriers of BRCA1 mutations (BRCA1(mut/+)) as well as the luminal progenitor population in Brca1-deficient mouse mammary glands is abnormally amplified. Remarkably, mouse Brca1(+/-) and human BRCA1(mut/+) progenitor cells are able to form colonies in vitro in the absence of progesterone, demonstrating a hormone-independent proliferative capacity. Our research has demonstrated that proliferation in BRCA1-deficient cells results in a DNA damage response (DDR) that activates a persistent NF-kappa B signal, which supplants progesterone/RANKL signaling for an extended time period. Thus, the transcriptional targets normally activated by RANKL that promote a proliferative response in luminal progenitors can contribute to the susceptibility of mammary epithelial cells to BRCA1-mutated breast cancers as a consequence of DDR-induced NF-kappa B. Together, these latest findings mark substantial progress in uncovering the mechanisms driving high rates of breast tumorigenesis in BRCA1 mutation carriers and ultimately reveal possibilities for nonsurgical prevention strategies. (C) 2017 AACR.