Chemotherapeutic Targeting of Fibulin-5 to Suppress Breast Cancer Invasion and Metastasis Simulated by Transforming Growth Factor-Beta
Annual rept. 15 Dec 2010-14 Dec 2011
CASE WESTERN RESERVE UNIV CLEVELAND OH
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Breast cancer is the second leading cause of cancer death in women in the United States. Invasion and metastasis are the most lethal characteristics of breast cancer and the leading cause of breast cancer-related death. TGF- normally inhibits breast cancer development by preventing mammary epithelial cell MEC proliferation, or by inducing MEC apoptosis. Mammary tumorigenesis counteracts the tumor suppressing activities of TGF- , thus enabling TGF- to stimulate breast cancer invasion and metastasis. Fundamental gaps exist in our knowledge of how malignant MECs overcome the cytostatic actions of TGF- , and of how TGF- stimulates the development and progression of mammary tumors. These knowledge gaps have prevented science and medicine from implementing treatments effective in antagonizing the oncogenic activities of TGF- in developing and progressing breast cancers. We recently discovered that the expression and activity of the TGF- gene target, Fibulin-5 FBLN5, potentiates TGF- stimulation of invasion and epithelial-mesenchymal transition EMT in normal and malignant MECs in vitro, and more importantly, enhances the growth and pulmonary metastasis of mammary tumors in mice. Interestingly, we find that FBLN5 incorporates into active TGF- receptor complexes in a 3 integrin-dependent manner, an event associated with the activation of intracellular signaling by TGF- . Based on these and other compelling findings, we hypothesized that inactivating FBLN5 function will prevent the conversion of TGF- from a suppressor to a promoter of breast cancer growth and invasion, thereby alleviating breast cancer development and progression stimulated by TGF- . The goals of this project are to determine the molecular mechanisms that mediate incorporation of FBLN5 into active TGF- receptor complexes, and to determine the role of FBLN5 in mediating 3 integrin and Src activation, leading to oncogenic signaling by TGF- in normal and malignant MECs.
- Anatomy and Physiology
- Medicine and Medical Research