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Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes

Abstract

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 expression is reduced in invasive breast cancer as compared with normal mammary epithelium. Because single nucleotide polymorphisms (SNPs) in regulatory genes have been implicated in risk and age at diagnosis of breast cancers, systematic SNP association studies were performed on TSC1 and TSC2 SNPs for their associations with clinical features of breast cancer. TSC1 and TSC2 haplotypes were constructed from genotyping of multiple loci in both genes in healthy volunteers. 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 based on haplotype frequencies. Genotyping for five TSC1 and one TSC2 loci were performed on genomic DNA from 1,137 women with breast cancer. This study found that for TSC1 rs7874234, TT variant carriers had a 9-year later age at diagnosis of estrogen receptor positive (ER+), but not ER−, ductal carcinomas (P = 0.0049). No other SNP locus showed an association 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 receptor element (ERE) site, resulting in increased TSC1 transcription and subsequent inhibition of mTOR.

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Abbreviations

TSC1:

Tuberous sclerosis 1

TSC2:

Tuberous sclerosis 2

SNP:

Single nucleotide polymorphism

ER:

Estrogen receptor

ERE:

Estrogen receptor element

mTOR:

Mammalian target of rapamycin

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Acknowledgments

We would like to thank all of the study participants at the Stacy Goldstein Breast Cancer Center at The Cancer Institute of New Jersey, as well as the researchers at the CINJ Tissue Analytic Services who provided support for sample collection, storage and distribution, Joseph Miktus and Jacqueline Harris. This work was supported by the Breast Cancer Research Foundation (Hirshfield/Levine), Ohl Foundation (Toppmeyer), New Jersey Commission on Cancer Research (Vazquez), and the Ruth Estrin Goldberg Memorial for Cancer Research (Hirshfield).

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Correspondence to Kim M. Hirshfield.

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Mehta, M.S., Vazquez, A., Kulkarni, D.A. et al. Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes. Breast Cancer Res Treat 125, 861–868 (2011). https://doi.org/10.1007/s10549-010-1062-1

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  • DOI: https://doi.org/10.1007/s10549-010-1062-1

Keywords

  • Breast cancer risk
  • SNP
  • TSC1/TSC2
  • Case study