Chemotherapeutic Targeting of Fibulin-5 to Suppress Breast Cancer Invasion and Metastasis Stimulated by Transforming Growth Factor-Beta

Abstract

Abstract : The primary objective of this application is to establish how Fibulin-5 enhances the oncogenic activities of TGF-beta, particularly its ability to stimulate breast cancer invasion and metastasis. We hypothesized that inactivating Fibulin-5 function will prevent the conversion of TGF-beta from a suppressor to a promoter of breast cancer growth and invasion, thereby alleviating breast cancer development and progression stimulated by TGF-beta. Major findings of the past funding cycle include the ability of Fibulin-5 to (i) bind integrins on mammary epithelial cells (MECs) independent of its integrin-binding RGD motif; (ii) interact physically with TGF-beta and enhance its presentation to TGF-beta receptors; (iii) promote epithelial-mesenchymal transition in an integrin-independent manner in part by stimulating the expression of Cox-2, PAI-1, and MMP-9; (iv) enhance MEC proliferation by activating FAK and ERK1/2; and (v) induce MEC resistance to apoptosis and anoikis by stimulating NF-kappaB activation, by inducing survivin and xIAP expression, and by repressing TNF-alpha expression. Finally, we determined that Fibulin-5 expression is greatly augmented during breast cancer progression, particularly at the point when malignant MECs acquire metastatic phenotypes. This important finding implicates Fibulin-5 as a potential marker for breast cancer metastasis and reinforces the need to target Fibulin-5 chemotherapeutically in patients with metastatic disease.