Poster abstracts

Poster number 50 submitted by Anisha Mathur

Constitutive activation of PDGFR-alpha in fibroblasts leads to defective growth of murine mammary glands

Anisha Mathur (Molecular and Cellular Biochemistry, Ohio State University), Gina M. Sizemore (Molecular and Cellular Biochemistry, Ohio State University), Anthony J. Trimboli (Molecular Virology, Immunology and Medical Genetics, Ohio State University), Gustavo Leone (Molecular Virology, Immunology and Medical Genetics, Ohio State University), Michael C. Ostrowski (Molecular and Cellular Biochemistry, Ohio State University)

Abstract:
Breast cancer is a leading cause of cancer-related mortality in women in the United States, despite the development of targeted therapies and earlier diagnoses. One of the major confounding factors in the treatment of this disease is the cellular heterogeneity of the mammary gland. Fibroblasts are cells of mesenchymal origin that are critical for wound healing and are an important component of normal mammary gland microenvironment. In the past decade, fibroblasts have been implicated in accelerating tumor progression. Platelet derived growth factor receptor alpha (PDGFR-α) is a targetable cell surface receptor that is chiefly expressed in mesenchymal cell populations, such as fibroblasts. While mutations in PDGFR-α were shown to be a poor prognostic factor in glioblastomas and Gastro-intestinal stromal tumors, the role of stromal PDGFR-α activation in mammary gland development and mammary carcinomas is yet to be explored. Thus, in this study we are exploring the role of fibroblast-specific PDGFR-α activation in both mammary gland development and cancer using genetic mouse models. We found that constitutive activation of PDGFR-α specifically in fibroblasts alters murine mammary ductal growth. Mutant mice have fewer ducts that fail to grow normally in the mammary fat pad. Mammary glands from these mice have decreased number of ducts, increased extra-cellular matrix (ECM) and increased fibroblast numbers. Stromal PDGFR-α activation also causes increased proliferation of mammary ductal (epithelial) cells suggesting that stromal PDGFR-α activation in combination with oncogenic hits in the epithelium can lead to increased tumor growth. Furthermore fibroblasts derived from the mutant mammary glands have increased levels of AKT, JNK and ERK, which are important pro-tumor pathways in fibroblasts. The mutant mammary fibroblasts also have decreased levels of Transforming Growth Factor- beta (TGF-β 2 and 3) RNA. This observation suggests that TGF-β ligands are potentially a novel downstream target of PDGFR-α signaling in fibroblasts. Since TGF-β biology is very important in both mammary gland development and cancer, our data further supports the hypothesis that stromal PDGFR-α might be a key regulator of mammary gland development and subsequently, play a role in mammary carcinomas.

Keywords: PDGFR, breast cancer, mammary gland development