"Role of IGF-1 in the CCN6-dependent regulation of ZEB1 in benign and breast cancer cells"

CABANILLAS AM , LORENZATTI G, PAL A, & KLEER CG

Ann Arbor, Michigan, USA

Simposio; 8th Annual Pathology Research Symposium, School of Medicine, University of Michigan; 2009

School of Medice, University of Michigan, USA

Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. The primary cause of death in patients with breast cancer is the development of metastasis, a process that is still poorly understood. Characterizing genes that regulate the growth and metastatic ability of breast cancer may identify novel biomarkers to help clinicians guide current treatments, and may offer new targets for therapy. We have identified CCN6 [ WISP3 ( Wnt-1 induced signaling protein 3)] as being down-regulated in tissue samples of breast cancers with high metastatic ability. We showed that CCN6 has tumor inhibitory functions in breast cancer in vivo and in vitro. We discovered that CCN6 interferes with the growth effects of IGF-1. Recently, our laboratory made the novel observation that inhibition of CCN6 in benign breast epithelial cells causes an epithelial to mesenchymal transition (EMT) with marked down upregulation of ZEB1. ZEB1 has been demonstrated to be a crucial player in the process of EMT. In order to make a dramatic impact on this disease, we need to understand the basic biology of breast cancer and subsequently target the particular pathways involved. Our central hypothesis is that CCN6 plays a causal role in breast cancer invasion and metastasis by regulating EMT through ZEB1 expression regulated by IGF1 signaling pathway. The specific aims of this project are to determine the role of IGF-1 signaling and CCN6 in regulating the expression of ZEB1 in benign and malignant breast cell lines and to investigate the relevance of CCN6-mediated ZEB1 expression to EMT, breast cancer invasion and metastasis.