PRIMARY FACULTY

Mary Lou Cutler, Ph.D.
Professor
Pathology
 
4301 Jones Bridge Road
Bethesda MD 20814
Office: 301-295-3453
Fax: 301-295-1996
mcutler@usuhs.mil

Experimental evidence from human cancer, animal tumor models and in vitro tissue culture assays of transformation indicates that activation of the signal transduction pathway regulated by the Ras GTPases can play a critical role in the development of neoplasia. Activating mutations of the Ras proto-oncogene are common genetic alterations in specific human tumors. In addition to mutational activation of a Ras gene, the equivalent of an activated Ras signal may result from a loss of function of the gene(s) negatively regulating Ras signaling. Using an expression cloning assay I have isolated several novel cDNAs which have the property of suppressing Ras transformation; one of these genes, referred to as rsp-1/rsu-1, has been characterized in detail. Both biochemical and genetic approaches are being used to delineate the specific mechanism(s) by which this suppression occurs. The information gained from our studies will be important in understanding the regulation of signal transduction pathways controlling proliferation, differentiation and apoptosis in tumors as well as normal cells, and may suggest novel anti-neoplastic therapies.

A study of the Ras suppressor molecules as tumor suppressors requires the identification of human tumors in which these genes are mutated or silenced. To that end we have identified glioblastoma as a tumor in which Rsu-1 is altered. In collaboration with the Neurosurgery Service at Walter Reed Army Medical Center we are screening human CNS tumors for genetic changes in tumor suppressor genes which are located on human chromosome 10, including Rsu-1. Another specific application of our analysis of Ras suppressors is to define the role of these genes and their protein products on the regulation of growth factor-induced proliferation of human breast cancer cells. Our recent studies have determined that ectopic expression of Rsu-1 can inhibit the malignant potential of human breast carcinoma cell lines. This is a result of the induction of apoptosis/ programed cell death by Rsu-1.

Another focus of the research in the laboratory is determination of the role of the mitogenic peptides of the EGF family on mammary epithelial cell differentiation. Exposure of mammary epithelia to mitogens can inhibit differentiation and prevent apoptosis in response to the withdrawal of hormones. This process results in part from activation of the Ras signal transduction pathway and our studies have determined that inhibition of the Ras pathway enhances lactogenic differentiation of mammary epithelial cells by increasing phosphorylation and DNA binding of the transcription factor Stat5. Current studies are directed at identifying the specific signal transduction pathways involved in regulation of this process.

Selected Publications

Resources