Association Between Resistance to Mammary Cancer Development and Upregulation of DNA Damage Response Genes

ABSTRACT

Rat strains differ strikingly in susceptibility to cancer. The rat strain WKY is highly resistant, while the SPRDCu3 strain is susceptible to chemically-induced mammary cancer. We previously showed that two chromosome regions (from chromosomes 5 and 18) contain quantitative trait loci (QTLs) controlling mammary cancer susceptibility. Here we tested the hypothesis that mammary cancer resistance is associated with a prompt and efficient DNA damage response (DDR) leading to a robust anti-cancer barrier. We also hypothesized that an efficient response to carcinogenic [(7,12- dimethyl benz[a]anthracene (DMBA)] treatment could be accompanied by gene activation and changes in mRNA levels. We thus compared the mRNA levels of several genes involved in the DDR in the mammary tissue of DMBA-treated and control WKY, SPRD-CU3 and congenic female rats. Our observations show that DMBA-treatment induces a dramatic increase in the level of several DDR mammary tissue mRNAs in rat strains that are resistant to mammary cancer, but not in the susceptible SPRD-Cu3 strain. Some of the upregulated genes are tumour supressor genes, such as Tp53 and Brca1. Several genes involved in the DDR are thus subject to regulations impacting their mRNA level and our results strongly support the hypothesis that the DDR is a barrier in early tumorigenesis.