Abstract P6-02-03: TGF-b1-inducible protein BIGH3 (transforming growth factor beta-induced gene human clone 3): A new mechanism inducing breast cancer cell apoptosis

Abstract

Abstract Cancer development and progression is a complex process involving tumor cell mechanisms as well as tumor-host cell interactions. Using autocrine and paracrine mechanisms the cytokine TGF-b1 can influence cancer progression, in part through promoting the synthesis and secretion of extracellular matrix molecules. TGF-β1 strongly upregulates the gene TGFBI, which encodes a secretory protein named BIGH3. BIGH3 is an extracellular matrix, adhesion-class proapoptotic protein characterized by four fasciclin-1 (FAS1)-like domains, a cysteine-rich region and several different integrin-binding sequences. The C-terminus of BIGH3 encodes the integrin-binding peptides EPDIM and RGD. These sequences, and the integrin α3β1, have been implicated as important components of BIGH3-induced apoptosis. Breast cancer cells express the integrin α3β1, which is reported to play various roles including signaling, invasion and metastasis. Breast cancer cells and tumor-host cells express BIGH3 protein, which is expected to accumulate in the presence of TGF-β1. The above findings highlight the molecules TGF-β1 and α3β1 in tumor progression and are the basis for our hypothesis that BIGH3 protein itself is sufficient to induce an increase in breast cancer cell apoptosis. In order to test this hypothesis we utilized human breast cancer MCF-7 cells, human recombinant BIGH3 and TUNEL assays. Here, we show for the first time that exogenous human recombinant BIGH3 in cancer cell growth medium evokes a statistically significant increase in breast cancer cell apoptosis. A concentration curve shows that there is a direct relationship between the quantity of BIGH3 in the cells’ milieu and the number of cells undergoing apoptosis. This finding is consistent with receptor-ligand binding and indicates that BIGH3 is a potential target for breast cancer treatment. Importantly, in-house developed anti-BIGH3 antibody completely blocked apoptosis when compared to apoptotic cells in negative control conditions. Stimulation of BIGH3 gene expression in breast cancer cells, and providing exogenous BIGH3 to breast cancer cells, are expected to diminish breast cancer progression. Along this line, BIGH3 may be valuable as an agent for neoadjuvant or adjuvant therapy for human breast cancer patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-02-03.