The role of hyaluronan receptor RHAMM in breast carcinoma

grantor: University of TorontoHyaluronan (Hyaluronic acid, hyaluronate, HA), a ubiquitous extracellular matrix molecule, has been implicated in the process of cell motility and tumor progression. Its receptor RHAMM is critical for the locomotion and growth of tumor cells. RHAMM is an oncogene that regulates signaling through ras and controls MAP kinase (ERK) in murine fibroblasts. The purpose of this study is to understand whether RHAMM is involved in human breast cancer progression. It was found that HA production was correlated with the rate of invasiveness of human breast cancer cell lines 'in vitro' and most strongly predicted the ability of these cells to invade and metastasize in nude mice. Addition of 1 mg/ml of HA stimulated invasion of previously non-invasive cell lines that made little endogenous HA and further enhanced invasion of invasive cell lines. RHAMM was also shown to be involved in the motility and invasion in these cell lines 'in vitro' as indicated by peptide and antibody blocking studies. RHAMM occurred as at least two isoforms in breast cancer cells although the function of each isoform was not investigated. In breast cancer patients, overexpression of RHAMM in subsets of tumor cells within the primary tumors of two patient cohorts was significantly prognostic of poor outcome and enhanced the prognostic value of lymph node status. Metastatic cells within lymph nodes exhibited a significantly higher level of RHAMM expression than the primary tumors. Further, RHAMM expression was significantly correlated with overexpression of both ras and ERK in primary tumors. Although the increased levels of RHAMM expression in breast cancer cell lines cloned from several separate tumors against a heterogeneous background 'in vitro' did not correlate with either motility or invasion rate, or indeed with the presence of ras mutations, in the MCF-10A background cells lacking other mutations, however, the presence of an active mutant ras enhanced RHAMM expression. Therefore, these results indicate that RHAMM is commonly involved in the locomotion and invasion of human breast cancer cells, consistent with its ability to predict poor prognosis of breast cancer patients. RHAMM is therefore a cell motility regulator.Ph.D