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    Research Grants Awarded

    Clinical Implications of Rabphillin-3A-Like Gene Alterations in Breast Cancer

    Study Section:
    Population Specific

    Scientific Abstract:
    Background: The human ortholog of the Rabphillin-3A-like gene (RPH3AL), located at locus17p13.3 locus, was first identified, cloned and sequenced in medulloblastoma in 1999. Preliminary studies from our laboratory have, for the first time, identified several novel missense mutations of RPH3AL in breast adenocarcinomas (BACs). Specifically, a single nucleotide polymorphism at the -25 position (Cytosine to Adenine) in the 5’ untranslated region (5’UTR-25) of exon 2 has a strong association with regional lymph node metastasis. Hypothesis: We hypothesize that underlying genetic variations within the RPH3AL gene are contributing to the aggressive phenotypic features of BACs. To our knowledge, the role of the RPH3AL gene in the progression or clinical usefulness in BAC has not bee studied. Experimental Design: To test our hypothesis, in Specific Aim 1, we propose to evaluate prospectively collected primary sporadic BACs and matching benign frozen specimens from 100 patients for the mutational status of the RPH3AL gene by direct sequencing exons 1 through 9. Subsequently, the mutational profiles will be correlated with standard clinicopatholgic features and patient survival. Tissue sections of BACs evaluated for RPH3AL will be further assessed for phenotypic expression of key molecules of the cell-cycle (p53, p21waf-1, p27kip-1, and cycle E), proliferation (Ki67) and the apoptotic pathway (Bcl-2 and Bax) to assess the effects of different mutations within the RPH3AL gene. In Specific Aim2, we will perform microarray studies to examine differences in gene expression profiles among patients with different types of mutations in RPH3AL. To better understand the complex relationships between the different types of RPH3AL mutations and multiple factors which influence aggressive phenotypic features, we propose to use novel computational data mining tools. Anticipated Results and Implications: These findings should identify the patterns of molecular and morphologic features seen in aggressive BACs, which will aid in predicting aggressive behavior of the tumors, risk of disease recurrence and patient survival. Additionally, these findings may provide the infrastructure allowing large population based epidemiologic studies; subsequently, these studies will aid in designing appropriate therapeutic regimens for patients with breast cancer.

    Lay Abstract:
    Background : The recently identified human ortholog of the Rabphillin-3A-like gene (RPH3AL) will be assessed for clinical significance in breast adenocarcinomas (BACs). Preliminary studies from our laboratory have, for the first time, identified several novel missense mutations of RPH3AL in BACs. Specifically, a single nucleotide polymorphism (SNP) at the -25 position in the 5’ untranslated region (5’UTR-25) of this gene has a strong association with regional lymph node metastasis. Hypothesis: We hypothesize that underlying genetic variations within the RPH3AL gene, specifically, the SNPs at 5’UTR-25 are contributing to the aggressive phenotypic features of BACs. To our knowledge, the role of the RPH3AL gene in the progression or clinical usefulness in BAC has not bee studied. Methodology: To test our hypothesis, in Specific Aim 1 , we propose to evaluate prospectively collected primary sporadic BACs and matching benign frozen specimens from 100 patients for the mutational status of the RPH3AL gene. Subsequently, the mutational profiles will be correlated with standard clinicopatholgic features and patient survival. Tissue sections of BACs evaluated for RPH3AL will be further assessed for phenotypic expression of key molecules of the cell-cycle, proliferation and the apoptotic pathway to assess the effects of different mutations within the RPH3AL gene. In Specific Aim2 , we will perform microarray studies to examine differences in gene expression profiles among patients with different types of mutations in RPH3AL. To better understand the complex relationships between the different types of RPH3AL mutations and multiple factors which influence aggressive phenotypic features, we propose to use novel computational data mining tools. Implications: These findings should identify the patterns of molecular and morphologic features seen in aggressive BACs, which will aid in predicting aggressive behavior of the tumors, risk of disease recurrence and patient survival. These findings will provide the infrastructure allowing large population based epidemiologic studies. Subsequently, a simple test on DNA, extracted from white blood cells or frozen tissues obtained during biopsy or surgery of BAC patients, will determine the genetic status of the RPH3AL gene. This test will help the clinical oncologist in assessing the aggressiveness of the disease and might aid in designing appropriate therapeutic regimens for patients with breast cancer.