Roles of FGF-2 TGF Beta and TGF Beta Receptor 2 in Breast Cancer Dormancy

摘要

Basic Fibroblast growth factor is associated with ductal morphogenesis in mammary duct development and its expression is lost in breast cancer. We determined the expression of FGF-2 during different stages of mammary carcinogenesis in archived surgical specimens. FGF-2 was expressed in the majority of specimens from normal, benign and atypical hyperplasia, fibrocystic disease and carcinoma in situ, but its expression frequency dropped significantly in invasive cancer. Enforced re-expression of FGF-2 in breast cancer call lines suggested a causal role for a more differentiated phenotype, including decreased motility and invasiveness. The decreased motility was associated with constitutive and omnidirectional focal adhesion complex activation and rearrangement of actin filaments. In a separate project, we investigated a potential mechanism for dormancy and survival of microscopic metastases in the bone marrow. Our model suggests that FGF-2 in the marrow inhibits proliferation of well-differentiated breast cancer cells and inhibits their survival. FGF-2 induces the overexpression of integrins alpha 5 and beta 1, which in turn bind fibronectin in the microenvironment and initiate survival signaling in these no-proliferating cells, establishing a state of dormancy. The protection afforded by this interaction is specific and provides a potential target for therapeutic intervention.