Abstract 3278: Sustained multilocular adipose tissue phenotype in adult Brca1 mutant mouse mammary gland is correlated with an increase in BMP7

Abstract

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

Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas

“…The observation that Ccn6 fl/fl ;MMTV‐Cre mice mammary glands showed delayed age‐related involution with residual terminal end buds and brown fat after 8 months of age may shed light into preneoplastic progression. Defective age‐related involution with persistent brown adipose has been reported in mammary glands from adult Brca1 mutant mice prior to development of poorly differentiated carcinomas (Jones et al 2011). Recent studies in human tissues showed that defective age‐related lobular involution is significantly associated with increased risk for breast cancer (Milanese et al 2006; Radisky and Hartmann 2009).…”