Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk
Date
2007
Authors
Blackburn, Anneke
Hill, Linda Z.
Roberts, Amy L.
Wang, Jun
Aud, Dee
Jung, Jimmy
Nikolcheva, Tania
Allard, John
Peltz, Gary
Otis, Christopher
Journal Title
Journal ISSN
Volume Title
Publisher
American Society for Investigative Pathology
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.
Description
Keywords
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 screening
Citation
Collections
Source
American Journal of Pathology
Type
Journal article
Book Title
Entity type
Access Statement
License Rights
Restricted until
2037-12-31
Downloads
File
Description