Induction of a tumor-hostile breast cancer microenvironment by metformin



 DESCRIPTION (provided by applicant): With regard to breast cancer chemoprevention, few drugs have been developed to disrupt the autocrine/paracrine signaling circuits which maintain the tumor-supportive microenvironment. Chronic inflammatory signaling through PGE2 (prostaglandin E2) and proinflammatory cytokines play significant roles in mediating tumor progression by promoting cancer cell proliferation. The anti-diabetic drug metformin is associated with decreased incidence of breast cancer, exhibits anti-proliferative, anti-inflammatory, effects in experimental models. However, there are few studies investigating if metformin exposure can attenuate tumor promoting autocrine/paracrine inflammatory signals which condition the breast cancer microenvironment. For this study, the goal is to ascertain the impact of metformin-modulated inflammatory signaling in the tumor microenvironment and consequently on tumor progression. PGE2, Annexin A2, and growth and Differentiation Factor 15(GDF15) are each molecules which play a distinct role in cell-extrinsic signaling in cancer and inflammation. As such, the overall hypothesis is that metformin disrupts pro-neoplastic autocrine/paracrine inflammatory signaling in breast cancer by disrupting the PGE2/annexin A2/GDF15 signaling axis. As such, the specific aims of this study include: Aim 1 will test the hypothesis that metformin-conditioning leads to cell intrinsic and cell extrinsic inhibition of BCC proliferation and invasiveness in vitro and in vivo. Aim 2 will test the hypothesis that metformin modulates tumor-supportive inflammatory signaling in breast cancer microenvironment by repressing PGE2 and annexin A2 production, and by inducing of GDF15 expression. The long term goal of these studies will contribute to the development of metformin and similar "metabolic reconditioning drugs" as therapeutic/chemo-preventive agents by identifying the key signaling elements involved in their antineoplastic effects. More fundamentally, these studies will provide valuable insight into the intersection of metabolism and inflammation in neoplastic disease.