Journal article

RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers

Emma Nolan, Francois Vaillant, Daniel Branstetter, Bhupinder Pal, Goeknur Giner, Lachlan Whitehead, Sheau W Lok, Gregory B Mann, Kathy Rohrbach, Li-Ya Huang, Rosalia Soriano, Gordon K Smyth, William C Dougall, Jane E Visvader, Geoffrey J Lindeman



Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11..

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Awarded by Australian National Health and Medical Research Council (NHMRC)

Awarded by National Breast Cancer Foundation (Australia)

Awarded by VCA Early Career Seed Grant

Awarded by NHMRC Fellowships

Awarded by NHMRC Australia Fellowship

Awarded by National Breast Cancer Foundation

Funding Acknowledgements

We are grateful to the women who generously donated breast tissue for our studies and to the surgical, pathology and tissue bank colleagues for their substantial assistance and support. We thank L. Taylor, K. Shackleton, S. Nightingale and H. Liu for expert assistance; the Animal, FACS, Imaging and Histology facilities at WEHI; C. Perou and K. Hoadley for kind provision of the PAM50 subtypes; and A. Y. Rhee (Amgen Inc.) for assistance with the manuscript submission. We are grateful to H. Thorne and all kConFab staff, members and families for their contributions to this resource and to the Victorian Cancer Biobank (supported by the Victorian Government), which also provided coded breast tissue and data. We thank H. Yasuda for advice on the antibody to mouse RANKL and K. U. Wagner (Eppley Institute, Nebraska) for MMTV-Cre A mice. This work was supported by the Australian National Health and Medical Research Council (NHMRC) (grant numbers 1016701 (J.E.V. and G.J.L.), 1040978 (G.B.M., J.E.V. and G.J.L.) and 1054618 (G.K.S.)), NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS) (to WEHI; E.N., F.V., B.P., G.G., L.W., S.W.L., G.K.S., J.E.V. and G.J.L.), the Victorian State Government through the Victorian Cancer Agency and Operational Infrastructure Support, the National Breast Cancer Foundation (Australia) (grant numbers NC-13-32 and PS-15-042; to J.E.V. and G.J.L.); Amgen Inc. (J.E.V. and G.J.L.), the Qualtrough Cancer Research Fund (J.E.V. and G.J.L.), the Joan Marshall Breast Cancer Research Fund (J.E.V. and G.J.L.) and the Australian Cancer Research Foundation (to WEHI; E.N., F.V., B.P., G.G., L.W., S.W.L., G.K.S., J.E.V. and G.J.L.). E.N. is supported by a Cancer Council Victoria Scholarship and a Cancer Therapeutics CRC Top-Up Scholarship; B.P. is supported by a VCA Early Career Seed Grant 13035; G.K.S. and G.J.L. are supported by NHMRC Fellowships 1058892 (G.K.S.), 637307 (G.J.L.) and 1078730 (G.J.L.); and J.E.V. is supported by NHMRC Australia Fellowship 1037230.