Chemotherapeutic Targeting of Fibulin-5 to Suppress Breast Cancer Invasion and Metastasis Stimulated by Transforming Growth Factor-Beta
Final rept. 13 Dec 2011-13 Oct 2012
CASE WESTERN RESERVE UNIV CLEVELAND OH SCHOOL OF MEDICINE
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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 ERK12 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.
- Anatomy and Physiology
- Medicine and Medical Research