ABERRANT FUNCTION OF THE RAS SIGNAL-TRANSDUCTION PATHWAY IN HUMAN BREAST-CANCER

Although ras mutations are infrequent (approximately 5%) in breast cancers, there is considerable evidence that suggests that the pathways which Ras services may still be deregulated in breast cancer cells. The recent identification of many of the components of the Ras signal transduction pathway has defined a network of proto-oncogene proteins controlling diverse signaling events that regulate cell growth and differentiation. Consequently, mutations that perturb the function of any one component of this signal pathway may trigger the same oncogenic events as mutation of ras itself. Moreover, several Ras-related proteins have recently been demonstrated to possess the ability to trigger malignant transformation via signaling pathways shared with Ras proteins. Thus, it is possible that the aberrant function of Ras-related proteins may contribute to breast cancer development. Consequently, it is important not to dismiss the Ras pathway in the development of breast cancer merely because of the infrequent detection of mutations in ras itself, but rather to consider the influence of aberrations upstream or downstream of Ras and of certain Ras-related proteins in the development of breast cancer. Finally, the critical importance of components upstream and downstream of Ras provides additional targets for rational drug design approaches to block the aberrant function of Ras signaling in human tumors.