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    Research Grants Awarded

    Role of Delete in Malignant Brain Tumors 1 (DMBT1) in Breast Cancer Susceptibility

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Up to 27% of breast cancers can be genetic-linked but mutations in high-risk genes like BRCA1/2 only account for 5-10% of them, indicating most genetic cancer predispositions are caused by mutations in low-penetrance/low-risk alleles, which are common among the general population. p53 plays critical roles in inhibiting tumors in human and animals. p53 +/- women develop multiple tumors with predominant breast tumors. In mice, mammary tumors are common among BALB/c- Trp53 +/- females but rare among C57BL/6- Trp53 +/- . These mice provide valuable tools to study breast cancer genes due to their sensitized background of p53 -heterozygosity. A genome scan by genetic crossing of these mice mapped a recessive locus to a ~10Mb region on chromosome 7 linked to mammary tumor susceptibility in BALB/c. Comparative microarray gene screen of the interval identified Dmbt1 as a leading candidate. Northern analysis of mouse mammary glands and immunostaining of normal human breast tissues confirmed that low Dmbt1 gene/protein level is statistically associated with individuals with increased mammary tumors susceptibility in both mouse and human. Introducing Dmbt1 expression in BALB/c mammary epithelial COMMA-D cells stopped the cell growth. Reduction or loss of Dmbt1 was found in many epithelial cancers including breast cancer and it is proposed as a tumor suppressor. But its function related to cancer suppression is not clearly demonstrated. W e propose that Dmbt1 may inhibit tumor by controlling cell proliferation and high Dmbt1 level presents growth disadvantage to tumor cells. Experiments were designed to characterize the functions connecting Dmbt1 to cancer growth. 1. Examine the effect of Dmbt1 on cell growth by expressing Dmbt1 in COMMA-D cells and analyzing cell proliferation using flow cytometry. 2. Identify the DMBT1 protein domain(s) that inhibit proliferation by expressing selectively deleted fragments in COMMA-D followed by cell growth analysis. 3. Determine t he subcellular localization of DMBT1 or its fragments using biochemistry and microscopy. 4. Evaluate whether reducing DMBT1 enhances cell proliferation and tumor growth by inhibiting Dmbt1 expression in MCF-7 cells using siRNA and examine cell proliferation in vitro , tumor growth in vivo following cell transplantation into nude mice. The study will facilitate to identify a novel low-penetrance allele and determine the role of DMBT1 in cancer susceptibility and its long suspected tumor suppressing function.

    Lay Abstract:
    Increased breast cancer incidence among women with family history indicates a genetic link of breast cancer. Mutations in dominant, high risk genes (BRCA1/2) only account for 5-10% of the breast cancers, while twin studies suggests that ~27% are linked to genetic factors, indicating that most breast cancer predispositions are caused by mutations of relatively low risk, recessive genes, which are common among the general population. p53 mutation was found in nearly all human cancer types including breast tumor. In mice, mammary tumors are common in BALB/c females with a mutant p53 ( Trp53 +/- ) but rare in C57BL/6- Trp53 +/- mice, meaning that BALB/c are more sensitive to grow tumors compared to C57BL/6. Our goal is to discover other low penetrance genes that influence the risk of breast cancer in human using these mice. p53 mutation in these mice provides a sensitized background to study low risk genes. Genetic data from mice have mapped a recessive gene to a ~10Mb region on chromosome 7. Microarray gene screen within the interval identified Dmbt1 as a leading candidate. Further analysis in both mouse and human confirmed that low Dmbt1 level is statistically linked to increased breast cancer susceptibility. Introducing Dmbt1 into BALB/c mammary epithelial COMMA-D cells caused the cell to stop growth. Reduced or loss of Dmbt1 was found in many epithelial cancers including breast cancer and it is proposed as a tumor suppressor. But its function related to cancer suppression is not clearly demonstrated . We propose that Dmbt1 may inhibit tumor by controlling cell growth and high Dmbt1 level presents growth disadvantage to tumor cells. Experiments were designed to examine the functions that connect Dmbt1 to cancer development. 1. Examine the effect of Dmbt1 on cell growth by expressing Dmbt1 in COMMA-D cells and analyzing cell growth. 2. Identify the critical part of DMBT1 that inhibit growth by expressing selectively deleted fragments of DMBT1 in COMMA-D followed by cell growth analysis. 3. Determine t he localization of DMBT1 or its fragments in the cells using biochemistry and microscopy. 4. Evaluate whether reducing DMBT1 enhances cell and tumor growth by inhibiting Dmbt1 expression in MCF-7 cells and examine cell proliferation and tumor growth in mice. The study will facilitate to identify a novel low-risk allele, and will provide insight into the role of Dmbt1 in breast cancer susceptibility, tumor suppression and its value as a potential prognostic biomarker.