Prognostic Value of Ras Activation in Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: When a women is diagnosed with breast cancer, the patient and clinician need information both on the tumor status and the presence of biomarkers to guide the course of the treatment. Thus, there is a continual search for new breast cancer genes and proteins as a signatures of the disease. Our interest is in a well known cellular protein, called Ras. This oncogene (i.e., cancer promoting), when present as protein, relays growth signals from the cell surface to the nucleus. Ras can either be in an "active" or an "inactive" molecular form. Only about 5% of human breast cancers have an activating mutation in Ras, suggesting that Ras itself is generally not involved in breast cancer pathogenesis. However, the epidermal growth factor (EGF) and HER-2/neu receptors are each over expressed in 20-40% of breast cancers, and both of these receptors signal through Ras. Thus, the presence of Ras, especially the "active" form of Ras, could be clinically significant. 
 
 
 
 
 
 
 
 In previous work using a novel patented assay, we found that Ras showed increased activation in 12 of 20 breast cancers, and the increased Ras activation appeared to be secondary to over expression of the EGF and ErbB-2 receptors. Over a four year follow-up period, metastases have developed in four of the 12 patients with increased Ras activation, and in only one of the eight patients with low Ras activation. Using BCRP funding we plan a collaborative project to expand our observations and, perhaps, set the stage for a more widespread use of an "activated Ras" assay in clinical medicine. 
 
 
 
 
 
 
 
 Our objectives are to measure Ras activation in 300-400 human breast cancers over three years, and to follow the patients for at least five years post-operatively to determine if increased Ras activation predicts a higher rate of recurrence and/or development of metastases. EGF and HER-2/neu expression will be assessed in these tumors, but there are several advantages to measuring Ras activation compared to only assessing growth factor receptor expression. Our approach and rationale has several elements. First, we will measure Ras activation by a quantitative biochemical assay. Second, we have developed an instrument to automate the Ras activation measurements, which will ultimately allow the assay to be performed in clinical laboratories. Third, Ras is downstream of, not just the EGF and ErbB-2 receptors, but of other growth factor receptors as well. Thus, we think that measuring Ras activation provides more global information on the status of the tumor, compared to studying single cellular receptors. Fourth, high growth factor receptor expression may not always lead to Ras activation depending on the concentration of ligands in the tumor tissue. For the above described studies, we will use a patented, highly sensitive assay that can measure ratios of GTP or GDP bound to Ras. This assay involves precipitation of Ras using antibodies, and we need to use freshly obtained biopsy samples. In other assays, we will determine the expression of the EGF and HER-2/neu receptors by immunohistochemical (IHC) staining, and amplification of the HER-2/neu gene will be assessed by FISH (fluorescence in situ hybridization).
 
 
 
 
 
 
 
 If we find that Ras activation predicts a more malignant phenotype in breast cancer, then this will provide a strong rationale for both continued development and better therapeutic application of Ras inhibitors discovered by the pharmaceutical industry.