Breast tumours in BRCA1-mutation carriers likely arise from the luminal progenitor population, previously shown to be expanded in BRCA1 carriers and to exhibit aberrant growth properties in vitro. Previous studies have shown that oophorectomy, and possibly tamoxifen, reduce breast cancer risk in BRCA1-mutation carriers, potentially via the loss of paracrine mediated signalling to stem/progenitor cells. The TNF superfamily member RANKL signals through its cognate receptor RANK and has recently been implicated as the major paracrine effector of progesterone’s mitogenic action in the mouse mammary epithelium, and has been implicated in the development of hormone-driven mouse mammary carcinogenesis.
Here we assessed RANK and RANKL expression in human breast tumours and normal breast tissue from women harbouring mutations in BRCA1 and BRCA2. We found that breast tumours from women with BRCA1 mutations had a higher incidence of RANK expression and an higher overall H score compared to BRCA2 tumours and tumours from non-carriers. In normal breast tissue, RANK expression was observed exclusively in the luminal progenitor population (Lin-EpCAM+CD49F+) in BRCA1 tissue from prophylactic surgeries as well as in normal breast tissue from reduction mammoplasties. Studies are currently underway to assess the functional regulation of the luminal progenitor population by RANKL, as well as to determine the effects of RANKL inhibition in both normal human breast and BRCA1-mutated breast cancer.