Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.

A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. The aim of the present investigation was to characterize the mammary adipose phenotype from Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We observed that histological sections of mammary tissue from adult Brca1 mutant mice abnormally display small, multilocular adipocytes that are reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA levels in the Brca1 mutant mice were elevated greater than 50-fold compared to age-matched mammary glands from wildtype mice. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity. Therefore, we also demonstrated that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice displayed regions of increased vascularity as evidenced by a significant increase in the protein expression of CD31, a marker for angiogenesis. This Brca1 mutant mouse model should provide a physiologically relevant context to determine whether brown adipose tissue can play a role in breast cancer development.

A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. Mammary epithelial cells are surrounded by an environment of supporting cell types, including the extracellular matrix, fibroblasts, and adipose tissue. Recent studies have demonstrated that this surrounding environment is an important regulator of tumor cell fate. The aim of the present investigation was to characterize the mammary adipose phenotype in the mammary gland of the Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We have observed sustained deposition of multilocular lipids in the mammary fat pad of Brca1 mutant mouse from puberty into adulthood that was reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular mammary adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA in the Brca1 mutant mice was elevated greater than 50-fold over levels seen in the age-matched mammary glands from wildtype mice. To gain insight into the origin of the multilocular adipocyte phenotype in the Brca1 mutant mouse mammary gland, we measured the expression of PRDM16, a regulator of brown fat differentiation. PRDM16 mRNA expression was increased 2-fold in Brca1 mutant mouse mammary gland compared to wildtype mice. Additionally, we show that protein levels of the bone morphogenetic protein 7 (BMP7), a protein known to induce brown adipogenesis in subcutaneous white adipose tissue, is significantly increased in mammary glands from Brca1 mutant mice compared to wildtype mice. These findings suggest that BMP7 could play a role in the sustained brown adipose tissue phenotype observed in adult Brca1 mutant mice. Interestingly, BMP7 has also been implicated in breast cancer pathogenesis and has been shown to induce breast cancer cell migration and invasion. We also demonstrate that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice has increased vascularity, a characteristic that is favorable for tumor development. Given that adipose tissue is the major contributor to the volume of the breast, it is critical to determine whether the sustained deposition of multilocular brown adipocytes in the mammary gland can impact breast cancer development. This Brca1 mutant mouse model should provide a physiologically relevant context to further examine the role of the plasticity of adipose tissue in breast cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3278. doi:1538-7445.AM2012-3278

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