Large population studies such as the Women's Health Initiative and the Million Women Study have shown that hormone replacement therapy (HRT) is associated with an increased risk of incident and fatal breast cancer. In particular, synthetic progesterone (progestins) used by millions of women for HRT and contraceptives markedly increase the risk of incident and fatal breast cancer. We have identified a key mechanism in how synthetic sex hormones can directly affect mammary cells leading to an increased risk of breast cancer.

The research built on our previous work where we provided the first genetic evidence that a molecule called RANKL is essential for bone turnover via osteoclasts in healthy individuals and bone loss in millions of patients suffering from osteoporosis or rheumatoid arthritis. We then found that RANKL and its receptor RANK controls the formation of milk-producing cells during pregnancy, a finding that provided a rationale why sex hormones regulate bone metabolism. This led us to propose that RANKL might be the link between sex hormones and breast cancer. Recently, my group and Gonzalez-Suarez et al. have reported that the RANKLRANK system is indeed a key regulator of sex hormone (progestin)- and oncogene (Neu)-driven mammary cancer. Intriguingly, therapeutic inhibition of RANKL can reduce the incidence of hormone-driven breast cancer from 100% to ~10% in a mouse model. I propose a project that could fulfill the dream of eradication of breast cancer and could have immediate impact on prevention and treatment of breast cancer, i.e., to further explore the role of RANKL/RANK in mammary stem cell biology, breast cancer initiation, and metastases. Moreover, I propose to take the RANKL/RANK system into human breast cancer patients to provide a novel prognostic marker for breast cancer risk and a molecular rationale for the initiation of clinical trials using already approved RANKL blockade as a tool to prevent the onset of breast cancer. Validation of RANKL/RANK as critical molecules in breast cancer initiation, mammary stem cell biology, and metastasis and the recent generation of therapeutics directed to block RANKL will have a direct impact for breast cancer patients.

In addition, to capitalize on the breakthroughs in human genetics by many researchers, I further propose to take the next step into the post-genome era of cancer, i.e., to develop systems to rapidly assess the function of candidate genes in breast cancer pathogenesis and metastases. We will utilize the power of fly genetics to rapidly check the function of hundreds and even thousands of human candidate breast cancer genes in epithelial transformation and metastases. Moreover, my laboratory has developed an entirely novel tool, haploid mouse embryonic stem cells, for rapid validation of gene functions. Such haploid carry a single set of chromosomes and therefore can be used to generate a library of stem cells that carry complete mutations in essentially all protein coding genes. Combining this mutant haploid ES cell library with in vivo mammary cancer and metastases assays, we will be able to rapidly assess the role of candidate breast cancer genes. Our novel techniques will be made available to other scientists and clinicians with the hope to markedly accelerate breast cancer research in the future.