Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk

Anneke C. Blackburn, Linda Z. Hill, Amy L. Roberts, Jun Wang, Dee Aud, Jimmy Jung, Tania Nikolcheva, John Allard, Gary Peltz, Christopher N. Otis, Qing J. Cao, Reva St J. Ricketts, Stephen P. Naber, Jan Mollenhauer, Annemarie Poustka, Daniel Malamud, D. Joseph Jerry

Research output: Contribution to journalArticlepeer-review

Abstract

Low-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.

Original languageEnglish (US)
Pages (from-to)2030-2041
Number of pages12
JournalAmerican Journal of Pathology
Volume170
Issue number6
DOIs
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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