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Sigl et al. RANKL/RANK necessary for mammary tumor growth in Brca1 mice



DOI:10.1038/bonekey.2016.96

Sigl et al. generated two mouse models to investigate if RANKL/RANK, a key factor that stimulates osteoclast differentiation, plays a role in breast tumor activation in mice with the Brca1 mutation.

Control mice with the Brca1 mutation and normal RANK expression within their mammary epithelium showed widespread epithelial hyperplasia with high-grade and invasive mammary tumors. In contrast, mice in which RANK had been genetically ablated appeared normal and, on further investigation, were found to have only a small number of mammary intraepithelial neoplasias. Reducing the level of RANK expression using pharmacological inhibition also prevented the formation of pre-neoplastic lesions usually associated with the Brca1 mutation.

Studies in tissue from women with BRCA1 mutations showed that genetic variation within the RANK locus significantly increased the risk of breast cancer. Encouragingly, genetic blockade of RANK in vitro inhibited proliferation and expansion of progenitors and mutant stem cells from the mammary glands of women with the BRCA1 mutation.

Editor’s comment: These findings are unsurprising since RANKL/RANK are essential for the formation of a lactating mammary gland during pregnancy. Another recent paper confirmed inhibition of RANKL as a potential target for breast cancer prevention in BRCA1-mutation carriers. Taken together, these studies suggest that therapy with the RANKL inhibitor denosumab may be protective against breast tumors in BRCA1 carriers.


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