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Analysis of polymorphic variants in TSC1, TSC2 and GRM1 and their association with breast cancer phenotypes

Madhura Sreenath Mehta
B.A., Rutgers College, Rutgers University - 2003

Thesis Advisor: Kim M. Hirshfield, MD, PhD
Graduate Program in Molecular Genetics, Microbioloty & Immunology

CINJ Auditorium B
New Brunswick

Wednesday, April 20, 2011
10:00 a.m.


Cell growth, cell death and cell cycle progression are cellular functions highly regulated through a number of integrated cell pathways. Dysregulation through abnormal expression or function of pathway genes may lead to tumorigenesis. Because single nucleotide polymorphisms (SNPs) in regulatory genes have been implicated in risk and age at diagnosis of breast cancers, we performed SNP association studies in several genes upstream of mTOR (a cell growth regulator) for their associations with breast cancer phenotypes.
Given evidence of reduced TSC1 and TSC2 expression in invasive breast cancer as compared with normal mammary epithelium and the role of TSC1/2 in the mTOR pathway, SNP association studies with TSC1 and TSC2 were undertaken. SNPs were selected for further study using a bioinformatic approach. For TSC1 rs7874234, TT variant carriers had a 9-year later age at diagnosis of estrogen receptor positive (ER+), but not ER-, ductal carcinomas. No other SNP loci showed associations with age at diagnosis, nor any other breast cancer phenotype. TSC1 rs7874234 is hypothesized to be functional in ER+ breast cancer because the T allele, but not the C allele, may create an estrogen response element (ERE) site, resulting in increased TSC1 transcription and subsequent inhibition of mTOR.
Epidemiologic studies suggest a link between melanoma and breast cancer. Moreover, in the breast cancer cohort at CINJ, excluding a second breast malignancy, melanomas were the most common second malignancy. Given the associations between melanoma and breast cancer, SNPs in GRM1 (a gene involved in melanomagenesis) were also evaluated for associations with breast cancer clincopathologic variables. The GRM1 SNP rs6923492, resulting in a proline to serine substitution, associates with age at diagnosis in a pattern highly dependent upon hormone receptor status. Furthermore, genotype-specific differences in calcium release and ERK activation were observed in response to agonist treatment with L-quisqualate and antagonism of GRM1 with either riluzole or BAY 36-7620. The role of GRM1 in breast cell biology and the effect of this SNP have not been well described. Therefore, further characterization of the molecular mechanism of GRM1 and this SNP in breast cancer was undertaken.

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