Published online before print April 13, 2007

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(American Journal of Pathology. 2007;170:2030-2041.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060512

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^|| and D. Joseph Jerry^*

From the Department of Veterinary and Animal Sciences,^* Molecular and Cellular Biology Program, University of Massachusetts, Amherst, Massachusetts; the Pioneer Valley Life Sciences Institute, Springfield, Massachusetts; the Department of Pathology, Baystate Medical Center, Springfield, Massachusetts; the Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, California; the New York University College of Dentistry,|| New York, New York; and Molecular Genome Analysis,^¶ German Cancer Research Center, Heidelberg, Germany

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 significantly 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.

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