Modifiers of mammary tumorigenesis in p53 heterozygous mice

Breast cancer is the most frequent tumor type in women in the US. Breast cancer is also the most prevalent tumor type in The Li-Fraumeni Syndrome (LFS), caused by an inherited mutation in the tumor suppressor Trp53. A mouse model of LFS was created by inactivation of p53 in a C57BL/6 and 129/SV mixed background. These mice develop a range of tumors including sarcomas and lymphomas, but do not develop mammary tumors. The p53 null allele was then crossed into the BALB/c strain, and the BALB/c p53+/- mice developed mammary tumors. BALB/c mice are inherently more susceptible to spontaneous mammary tumors than C57BL/6 mice, which is amplified by p53 heterozygosity. Trp53+/-mice in a C57BL/6 background still have a mammary tumor incidence of \u3c1%. These data lead us to hypothesize that the BALB/c mice harbor modifiers that increase mammary tumorigenesis. We have established F1 and F2 crosses, as well as backcrosses to BALB/cJ (N2-BALB/cJ) and C57BL/6J (N2-C57BL/6J) strains. All cohorts developed mammary carcinomas in p53+/- females at 25% (F1), 18% (F2), 36% (N2-BALB/cJ), and 11% (N2-C57BL/6J), suggesting multiple loci dominantly and recessively contributed to mammary tumorigenesis. We have mapped two modifiers of mammary tumorigenesis in the BALB/cJ strain. Mtsm1 (mammary tumor susceptibility modifier), a dominant acting modifier, is located on chromosome 7. Mtsm1 is suggestive for linkage to mammary tumorigenesis (p=0.0011). We have analyzed the Mtsm1 region to locate candidate genes by comparing it to a rat modifier region, Mcs3, which shares synteny with Mtsm1. Expression data and SNPs were also taken into account. Five potential candidate genes within Mtsm1 are Aldh1a3, Chd2, Nipa2, Pcsk6, and Tubgcp5. The second modifier mapped is Mtsm2 , a recessive acting modifier. Mtsm2 is located on chromosome X and is significantly linked to mammary tumorigenesis (p=1.03 × 10-7). These modifiers do not account for all of the mammary tumors that develop in this model. Additional genotyping of mice with mammary tumors may reveal additional modifiers in BALB/c mice. Candidate genes within the Mtsm1 and Mtsm2 loci need to be tested to establish their role in mammary tumorigenesis.