Student Research: Xuefeng Ren

, Environmental Toxicology (Tox), 2007
Faculty Advisor: Helmut Zarbl

Multiple Genetic Factors Contribute to the Differential Genetic Susceptibility of Copenhagen and Fischer 344 Rats to Mammary Carcinogenesis


Different inbred rat strains vary widely in their genetic susceptibility to spontaneous and carcinogen-induced mammary carcinogenesis. To gain insight into the molecular mechanisms of differential genetic susceptibility, we used genetic linkage analysis ((F344 X Cop) F1 X F344)) N2 backcross progeny to identify loci and candidate genes that conferred genetic susceptibility to NMU-induced mammary carcinogenesis in the F344 rat. Two susceptibility loci were identified that located on Chr1 and Ch12. Within the locus on Chr12, we identified the rat fry homolog gene, in which a total of 22 single nucleotide polymorphisms were found between Cop and F344 rats, and two of them resulted in changes of amino acid of the rat fry protein. Further functional prediction and gene expression study suggested that the rat fry gene might be involved in regulation of the differential genetic susceptibility of Cop and F344 rat to mammary carcinogenesis.

As an alternative approach to elucidating the molecular basis for differential genetic susceptibility to mammary carcinogenesis, we generated and compared global gene expression profiles among normal mammary tissue of five inbred rat strains (Cop, F344, ACI, Buf/N and WF) and F1 (COP X F344) progeny. Our results suggested that the Prl signaling in the mammary glands are not only regulated at the genetic level, but also contribute to the mechanism of genetic susceptibility among inbred rat strains. We also conducted the genomic wide expression profiling comparison of mammary tissues between Cop and F344 rat at three different time points with or without NMU treatment. Lcn2 gene was expressed at dramatically higher levels in the Cop rat as compared to the F344 rat strain. Our further experiments showed that lcn2 inhibited the growth of oncogene-transformed cells by modulating the Hras-MAPK signaling pathway. Given the high levels of lcn2 expression in the Cop relative to susceptible F344 strain, these findings suggested that lcn2 may also play a role in suppressing the in vivo outgrowth of hras-initiated mammary cells in Cop rat. Taken together, these studies suggested that multiple genetic factors contributed to differential susceptibility to mammary carcinogenesis between resistant Cop and sensitive F344 rats.