Abstract 283: Osteopontin cleavage fragments drive FGFR1-mediated mammary tumorigenesis

Abstract

Abstract Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Over 40,000 women in the U.S. die of breast cancer annually. To reduce disease severity, it is important to study alterations in tumor cells and the microenvironment, which contribute to breast cancer development and progression. Recent studies show that aberrant expression of fibroblast growth factors and their receptors (FGFRs) have been linked to development of breast cancer. Specifically, FGFR1 enhances risk of tumor development. Studies illustrate that amplification of FGFR1 is linked to poor patient prognosis and poor response to clinical treatment. These observations suggest that FGFR1 may serve as a potential oncogene to promote breast cancer. To study the mechanisms of FGFR1-induced mammary tumorigenesis, we use a mouse mammary tumor virus-driven inducible model of FGFR1 activation. Previous studies demonstrated that FGFR1 activation promotes migration, invasion, and proliferation of mammary epithelial cells. The FGFR1 model represents a unique method in which the effects of FGFR1 activation on mammary epithelial cells can be measured during early stages of mammary tumorigenesis. Recent studies illustrate that FGFR1 activation in mammary epithelial cells promotes a localized proinflammatory response, which is important for the formation of early hyperplastic lesions. One inflammatory factor induced by FGFR1 activation is osteopontin, which is a secreted phosphoprotein known to promote breast cancer progression and facilitate macrophage recruitment and activity. We predict that osteopontin acts on both epithelial cells and macrophages to promote FGFR1-induced mammary tumorigenesis. The goal of this research is to identify functional differences between osteopontin cleavage fragments and full-length osteopontin. Receptor interactions and components of the tumor microenvironment suggest a possibility for different functions. Both cell culture and transgenic mouse models are being used to study the effects of osteopontin cleavage fragments on FGFR1-induced migration, invasion, and proliferation. Furthermore, interactions between osteopontin cleavage fragments and primary mammary epithelial cells as well as immune cells, including macrophages, are being studied using a novel 3-dimensional co-culture system. Studying functions of cleaved osteopontin will elucidate the mechanisms by which initiating oncogenic events, including aberrant growth factor signaling, contribute to tumor growth and progression. Results from this research will contribute to development of novel multi-targeted therapies that will inhibit early pro-tumorigenic events in both tumor cells and the surrounding microenvironment. Thus, understanding the effects of osteopontin on mammary tumorigenesis will make osteopontin an excellent tumor prognostic marker and potential biomarker for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 283.