Abstract 1498: Breast adipose mesenchymal stem cells and mammary fibrosis

Abstract Introduction: At a biochemical level, the most common symptom of aging and its related pathologies (i.e. cancer) is the accumulation of altered or abnormal proteins. Aberrant proteins can induce oxygen free radical generation and inflammation; additionally an abnormal inflammatory response can lead to over-production and deposition of extracellular matrix (ECM) components, leading to fibrosis. The linkage between fibrosis and cancer is well established in the lung; alternatively breast fibrosis is a less understood phenomenon. Fibrosis is characterized by the excess production and altered composition and crosslinking of the ECM. Myofibroblasts are the principal mediators of fibrosis, producing abundant ECM as well as inflammatory and angiogenic factors; chronic tissue fibrosis is associated with tumor development. Likewise, stromal cells within the breast tumor microenvironment can provide tumor-promoting effects. Yet, very little is known regarding the role of local-adipose mesenchymal stem cells (MSCs) in the development of cancer. Objectives: If breast density and fibrosis are both associated with less fat and more connective tissue, we reason that resident breast MSCs (b-MSCs) are chemoattracted toward mammary glandular elements where they trigger a desmoplastic response characterized by their transdifferentiation into myofibroblasts, rather than differentiating along an adipocytic lineage; thus proposing that b-MSCs, an understudied yet abundant stromal constituent, contribute early in the development of breast cancer. Moreover, if b-MSCs contribute to fibrosis, it is critical to understand and deter this early fibrotic initiation factor. Preliminary Data, Methodology, and Future Directions: Affymetrix data, qRT-PCR, and western blotting results reveal that undifferentiated b-MSCs constitutively express multiple matrix metalloproteinases and chemokine receptors, which could guide these stromal cells from local fat stores into the parenchyma, activating a cascade of events leading to fibrosis. qRT-PCR reveals b-MSCs express multiple members of the epidermal growth factor (EGF) receptor family, most notably HER1. Soluble heparin binding epidermal growth factor (HB-EGF) and EGF modestly effects b-MSC growth, but markedly enhances migration. Moreover, HB-EGF and EGF interfere with adipogenic differentiation. Future studies will analyze the fibrogenic response initiated by b-MSCs in co-culture with normal, pre-malignant and malignant breast epithelial cells and evaluate the effectiveness of the dipeptide, carnosine, on reducing fibrogenesis. Support: This work was supported by a DOD Breast Cancer Research Program Idea Award (BC094734) to L.E. 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 1498. doi:1538-7445.AM2012-1498