Research Project
6470015
DESCRIPTION (provided by applicant): Background: Scatter factor (SF) (hepatocyte growth factor) stimulates cell motility, invasion, epithelial morphogenesis, oncogenesis, and angiogenesis, via its receptor, the tyrosine kinase c-Met. SF and c-Met expression increase during breast cancer progression, and high levels of SF correlate with with invasion, angiogenesis, and poor prognosis. And SF protects epithelial and breast cancer cells against apoptosis and confers resistance to DNA damage. Preliminary Studies: During the initial period, we found that: 1) the SF protection involves signaling from c-Met -> p21Ras/PI3 kinase -> c-Akt/Pak1 -> forkhead FKHR; 2) the Grb2-associated binder Gab1, an adapter that transduces epithelial morphogenesis, inhibits this pathway upstream of c-Akt; and 3) apoptosis inhibition occurs, in part, upstream of the mitochondria and caspase activation. Using cDNA microarray analyses, we identified novel genes that may contribute to SF protection against the topoisomerase II inhibitor adriamycin: e.g., PKD1 (polycystin), 51C (an inositol 5-phosphatase), TOPBP1 (a topoisomerase II binding protein), and CIP4 (a cdc42-interacting protein). Hypothesis: SF protects breast cancer cells against DNA-damage by a specific c-Met signaling pathway that is negatively regulated by Gab1 and signaling phosphatases and that leads to altered expression of several novel genes. Aims: We propose to: 1) delineate the upstream pathways by which c-Met signals for cell survival in breast cancer cells, including the targets of c-Akt and the inhibitory roles of Gab1 and several signaling phosphatases; 2) elucidate the DNA damage-induced pre-mitochondrial apoptosis signaling events and the mechanism(s) by which they are blocked by SF, and determine the roles of inhibitor of apoptosis proteins (IAPs) and SMAC in SF cell protection; and 3) establish the roles of novel down-stream genes in SF protection against several types of DNA damage. Significance: These findings will provide new insights into how SF functions as a tumor survival factor for breast cancers. They may identify novel molecular targets for the design of strategies for radio/chemosensitization and chemoprevention of tumors. Since SF may ameliorate certain forms of organ injury, understanding how it inhibits apoptosis may also provide new targets for the treatment of developmental, inflammatory, or toxic disorders.
