title: Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk.
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 approximately 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.
authors.affiliation: Department of Veterinary and Animal Sciences, Molecular and Cellular Biology Program, Paige Laboratory, University of Massachusetts, 161 Holdsworth Way, Amherst, MA 01003-6410, USA.
authors.forename: Anneke C
authors.initials: AC
authors.lastname: Blackburn
authors.forename: Linda Z
authors.initials: LZ
authors.lastname: Hill
authors.forename: Amy L
authors.initials: AL
authors.lastname: Roberts
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Dee
authors.initials: D
authors.lastname: Aud
authors.forename: Jimmy
authors.initials: J
authors.lastname: Jung
authors.forename: Tania
authors.initials: T
authors.lastname: Nikolcheva
authors.forename: John
authors.initials: J
authors.lastname: Allard
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Otis
authors.forename: Qing J
authors.initials: QJ
authors.lastname: Cao
authors.forename: Reva St J
authors.initials: RS
authors.lastname: Ricketts
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Naber
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.forename: Annemarie
authors.initials: A
authors.lastname: Poustka
authors.forename: Daniel
authors.initials: D
authors.lastname: Malamud
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Jerry
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002135:Calcium-Binding Proteins; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012307:Risk Factors; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C114202:Dmbt1 protein, mouse; D009077:Mucins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins