INHERITED SUSCEPTIBILITY AND ACQUIRED ALLELIC IMBALANCE IN RAT MAMMARY CARCINOGENESIS

Individual genetically determined susceptibility to cancer as well as acquired epigenetic and genetic organ specific alterations are importa nt considerations in choosing target populations for chemopreventive t rials. These individual epigenetic and generic alterations can also se rve as potential biomarkers for chemoprevention clinical trials. In or der to model these potential markers for chemoprevention investigation s, we are examining a series of interrelated rat models. Inbred rats v ary in their susceptibility to mammary cancer induction by environment al agents. For example, the WF strain is highly susceptible to chemica lly induced mammary cancer while the Cop rdt is almost completely resi stant. The F344 is intermediate in susceptibility to chemically induce d mammary cancer. These differential susceptibilities are inherited in a dominant pattern. For example, resistance is due to the inheritance of Mcs gene(s) which likely act by altering the differentiation linea ge of mammary epithelial cells. As tumors form in the mammary glands o f these rats, they acquire additional epigenetic and genetic alteratio ns. Epigenetic initiation is a very frequent cellular event following carcinogen exposure which may predispose cells to genetic change inclu ding allelic imbalance. For example, following a standard dose of NMU or DMBA over 1% of cells are epigenetically initiated. During the carc inogenesis process, initialed cells may acquire genetic change such as oncogene activation and allelic imbalance. Interestingly, the pattern of allelic imbalance appears to be an inherited trait. For example, a non-random loss of heterozygosity (LOH) in rat chromosome 1 following DMBA only occurs in certain strains, such as Cop rats. Interestingly this change does not occur following initiation by ionizing radiation. It will thus be important to identify these epigenetic and genetic ev ents which underlie mammary carcinogenesis as well as determine their patterns of inherited predisposition and temporal occurrence. Such kno wledge is critical if we are to develop new molecular markers for chem oprevention trials. (C) 1997 Wiley-Liss, Inc.