NF-kappaB 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-kappaB ligand (RANKL) in 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 (BRCA1mut/+) as well as the luminal progenitor population in Brca1-deficient mouse mammary glands is abnormally amplified. Remarkably, mouse Brca1+/- and human BRCA1mut/+ 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-kappaB 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-kappaB. 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 non-surgical prevention strategies.

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