Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk.
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.
Blackburn
Anneke C
AC
Department of Veterinary and Animal Sciences, Molecular and Cellular Biology Program, Paige Laboratory, University of Massachusetts, 161 Holdsworth Way, Amherst, MA 01003-6410, USA.
Hill
Linda Z
LZ
Roberts
Amy L
AL
Wang
Jun
J
Aud
Dee
D
Jung
Jimmy
J
Nikolcheva
Tania
T
Allard
John
J
Peltz
Gary
G
Otis
Christopher N
CN
Cao
Qing J
QJ
Ricketts
Reva St J
RS
Naber
Stephen P
SP
Mollenhauer
Jan
J
Poustka
Annemarie
A
Malamud
Daniel
D
Jerry
D Joseph
DJ
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
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C114202:Dmbt1 protein, mouse; D009077:Mucins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins