Abstract 1173: Polymorphic variants in TSC1 associate with breast cancer phenotypes
Authors: Mehta Madhura S. , Vazquez Alexei , Hirshfield Kim M. 
Published: February 2011

Abstract
Background: TSC1 acts coordinately with TSC2 in a complex to inhibit mTOR, an emerging therapeutic target and known promoter of cell growth and cell cycle progression. Perturbation of the mTOR pathway, through abnormal expression or function of pathway genes, could lead to tumorigenesis. TSC1 and TSC2, expressed in normal mammary epithelial cells, have reduced expression in invasive breast cancer. Mutations in either TSC1 or TSC2 cause tuberous sclerosis, a disorder characterized by hamartomas affecting multiple organ systems. Single nucleotide polymorphisms (SNPs) have been implicated in risk and age at diagnosis of breast cancers. Our laboratory has previously reported on polymorphisms in p53 pathway genes that associate with age at diagnosis of breast cancer and on how these associations depend on breast cancer phenotypes. Systematic SNP association studies have yet to be performed on TSC1. We evaluated SNPs in TSC1 for their associations with clinical features of breast cancer.
Experimental Procedure: Eighteen TSC1 loci were genotyped in DNA from healthy volunteers and a haplotype constructed. SNPs were selected for further study using a bioinformatics approach based on SNP associations with drug response in NCI-60 cell lines and evidence of selection bias for haplotype frequencies. TaqMan allelic discrimination assays were performed on genomic DNA isolated from whole blood from over 900 women, recruited through CINJ clinics for four SNPs.
Results: We evaluated four TSC1 loci as potential genetic biomarkers of breast cancer risk and outcomes: IVS1+6929 (SNP1), IVS19+68 (SNP2), Ex22+3564G&gt;A (SNP3) and IVS2+5685 (SNP4). We found that postmenopausal women who were TT carriers of SNP1, had a 7 year later age at diagnosis of ER+, but not ER-, ductal carcinomas (p=0.027). We also found that SNP1 may modify the effect of BMI on age at diagnosis. Although high BMI is thought to increase risk for developing breast cancer; in our cohort, it is significantly associated with a 4 year later age at diagnosis of breast carcinoma. This effect was exaggerated in TT carriers of SNP1 whereby TT carriers had a 10.9 year later age at diagnosis as compared with CC carriers (p=0.007). None of the four TSC1 SNPs showed association with recurrence or other breast cancer phenotypes. SNPs 2-4 showed no association with age at diagnosis.
Conclusions: We have shown that TSC1 SNP1 may have a functional role in age at diagnosis of ER+, but not ER-, breast cancer and may be modified by BMI. We postulated that the presence of the T allele, but not the C allele, creates a site for estrogen receptor (ER) to bind an ERE in TSC1, resulting in activation of TSC1 transcription and increased inhibition of mTOR. Modulation of age of diagnosis by BMI may be further enhanced due to correlations between BMI with altered hormone levels.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1173.