The overall goal of this continuing project is to further characterize and quantify cellular and molecular carcinogenic events in the rat NMU- mammary carcinogenesis model. Characterization will include the integration of these events into the multistage initiation- promotion/progression model.
Aim 1 will quantify the probability of a mammary cell with activated ras progressing to a mammary carcinoma. The effects of various factors on this probability of progression will also be explored.
Aim 2 will seek to identify non-ras initiation events induced by NMU in a mammary specific assay. In addition, since ras activation does not transform mammary cells by a single step mechanism, we will begin to identify genetic changes which may complement ras in transforming mammary cells.
Aim 3 will investigate the mechanism underlying the observation that mammary carcinomas induced by NMU with activated ras oncogenes only have activated H-ras and never activated K- ras. We will seek the basis for this mammary-oncogene specificity by determining if this specificity results from differential mutagenesis, protein function, or oncogene expression for ras family members. The methodology to be used to accomplish these three aims integrates molecular and biological assays including for example: PCR analysis of ras activation, quantitative limiting dilution assay of mammary clonogenic stem-like cells, a newly developed method to insert specific genes into in situ mammary cells under the control of various promoters, and the construction and analysis of transgenic rat models. The experiments proposed will yield new information regarding the role of carcinogen induced molecular events such as oncogene activation in the biological process of carcinogenesis.
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