Blackburn, AnnekeHill, Linda Z.Roberts, Amy L.Wang, JunAud, DeeJung, JimmyNikolcheva, TaniaAllard, JohnPeltz, GaryOtis, ChristopherCao, QingRicketts, Reva St. J.Naber, Stephen PMollenhauer, JanPoustka, AMalamud, DanielJerry, Joseph2015-12-070002-9440http://hdl.handle.net/1885/18019Low-penetrance breast cancer susceptibility alleles seem to play a significant role in breast cancer risk but are difficult to identify in human cohorts. A genetic screen of 176 N2 backcross progeny of two Trp53+/- strains, BALB/c and C57BL/6, which differ in their susceptibility to mammary tumors, identified a modifier of mammary tumor susceptibility in an ∼25-Mb interval on mouse chromosome 7 (designated SuprMam1). Relative to heterozygotes, homozygosity for BALB/c alleles of SuprMam1 significantly decreased mammary tumor latency from 70.7 to 61.1 weeks and increased risk twofold (P = 0.002). Dmbt1 (deleted in malignant brain tumors 1) was identified as a candidate modifier gene within the SuprMam1 interval because it was differentially expressed in mammary tissues from BALB/c-Trp53+/- and C57BL/6-Trp53+/- mice. Dmbt1 mRNA and protein was reduced in mammary glands of the susceptible BALB/c mice. Immunohistochemical staining demonstrated that DMBT1 protein expression was also significandy reduced in normal breast tissue from women with breast cancer (staining score, 1.8; n = 46) compared with cancer-free controls (staining score, 3.9; n = 53; P < 0.0001). These experiments demonstrate the use of Trp53+/- mice as a sensitized background to screen for low-penetrance modifiers of cancer. The results identify a novel mammary tumor susceptibility locus in mice and support a role for DMBT1 in suppression of mammary tumors in both mice and women.Keywords: protein dmbt1; tumor suppressor protein; unclassified drug; Dmbt1 protein, mouse; mucin; protein p53; allele; animal model; article; breast cancer; cancer risk; cancer susceptibility; chromosome 7; controlled study; female; gene mapping; genetic screening200710.2353/ajpath.2007.0605122015-12-07