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  • 1
    Abstract: According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C〉T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A〉C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 19830809
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  • 2
    Keywords: brain ; CANCER ; EXPRESSION ; tumor ; human ; COHORT ; RISK ; GENE ; PROTEIN ; TISSUE ; TUMORS ; MICE ; TISSUES ; SUPPRESSION ; chromosome ; SUSCEPTIBILITY ; SUSCEPTIBILITY LOCUS ; BREAST ; breast cancer ; BREAST-CANCER ; MOUSE ; WOMEN ; cancer risk ; EPITHELIAL-CELLS ; pathology ; BRCA2 MUTATIONS ; protein expression ; BRAIN-TUMORS ; ALLELE ; TUMORIGENESIS ; CANCER SUSCEPTIBILITY ; GLAND ; HOMOZYGOSITY ; INTERVAL ; LOCUS ; USA ; POPULATION-BASED SERIES ; CANDIDATE ; INCREASED RISK ; CANCER-RISK ; mammary ; breast cancer susceptibility ; BACKGROUND ALTERS ; DISTAL CHROMOSOME-7 ; MUTANT P53-INDUCED IMMORTALIZATION ; N2
    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 similar to 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). Dmbtl (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 inammary tumors in both miceandwomen
    Type of Publication: Journal article published
    PubMed ID: 17525270
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