PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

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Altered Genes Expression In Rat Mammary And Mouse Lung Models: Comparison With Altered Expression In Humans And Modulation of Gene Expression by Known Chemopreventive Agents. Substantial genetic instability, as reflected in LOH or aneuploidy, appear to be a hallmark of most human cancers and even many preinvasive lesions, e.g. DCIS in breast, dysplastic lesions in lung, colon adenomas, CIN 2 and CIN 3 in cervix etc. In contrast a more limited number of oncogenes or tumor suppressor genes [P53, Ki Ras, APC, Rb etc] have been fully characterized for possible mutations and most cancers are characterized for a limited number of mutations in these same genes. The objective of this study is to use methodologies which allow the simultaneous examination of altered RNA levels in hundreds of genes simultaneously and which additionally allows one to clone and perform partial sequencing of the cDNAs coding for these genes in a relatively easy manner. The rat mammary tumor model is being used to readily determine whether effective chemopreventive agents alter levels of the presumptive RNAs identified in the screening mode. 1) Extensive screening of MNU rat mammary tumors for altered expression of various RNAs 2) Compare using a more limited subset of RNAs (40-50) altered expression of these genes in rat mammary tumors induced by MNU, DMBA and tumors induced by radiation plus estradiol 3) Determine again employing a limited number of RNAs whether one sees a substantially different pattern in MNU induced tumors bearing a mutation in the HaRas oncogeny versus those tumors not bearing a mutation in the HaRas oncogene 4) Determine employing a subset of RNAs whether the expression of these genes is modulated by known chemopreventive agents.