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


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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Fig. 1
Fig. 2



Tuberous sclerosis 1


Tuberous sclerosis 2


Single nucleotide polymorphism


Estrogen receptor


Estrogen receptor element


Mammalian target of rapamycin


  1. Key TJ, Verkasalo PK, Banks E (2001) Epidemiology of breast cancer. Lancet Oncol 2(3):133–140

    CAS  Article  PubMed  Google Scholar 

  2. Bennett IC, Gattas M, Teh BT (1999) The genetic basis of breast cancer and its clinical implications. Aust N Z J Surg 69(2):95–105

    CAS  Article  PubMed  Google Scholar 

  3. Turnbull C, Rahman N (2008) Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet 9:321–345

    CAS  Article  PubMed  Google Scholar 

  4. Dunning AM et al (1999) A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8(10):843–854

    CAS  PubMed  Google Scholar 

  5. Bond GL et al (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66(10):5104–5110

    CAS  Article  PubMed  Google Scholar 

  6. Rubinstein WS (2008) Hereditary breast cancer: pathobiology, clinical translation, and potential for targeted cancer therapeutics. Fam Cancer 7(1):83–89

    Article  PubMed  Google Scholar 

  7. Martin M (2006) Molecular biology of breast cancer. Clin Transl Oncol 8(1):7–14

    CAS  Article  PubMed  Google Scholar 

  8. Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412(2):179–190

    CAS  Article  PubMed  Google Scholar 

  9. de Vries PJ, Howe CJ (2007) The tuberous sclerosis complex proteins—a GRIPP on cognition and neurodevelopment. Trends Mol Med 13(8):319–326

    Article  PubMed  Google Scholar 

  10. Orlova KA, Crino PB (2010) The tuberous sclerosis complex. Ann N Y Acad Sci 1184:87–105

    Google Scholar 

  11. Yu JJ et al (2009) Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc Natl Acad Sci USA 106(8):2635–2640

    CAS  Article  PubMed  Google Scholar 

  12. York B et al (2005) Cross-talk between tuberin, calmodulin, and estrogen signaling pathways. FASEB J 19(9):1202–1204

    CAS  PubMed  Google Scholar 

  13. Sampson JR (2009) Therapeutic targeting of mTOR in tuberous sclerosis. Biochem Soc Trans 37(Pt 1):259–264

    CAS  Article  PubMed  Google Scholar 

  14. Meric-Bernstam F, Gonzalez-Angulo AM (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27(13):2278–2287

    CAS  Article  PubMed  Google Scholar 

  15. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945

    CAS  Article  PubMed  Google Scholar 

  16. Franz DN et al (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59(3):490–498

    CAS  Article  PubMed  Google Scholar 

  17. Jiang WG et al (2005) Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: the role of promoter methylation of TSC genes. Eur J Cancer 41(11):1628–1636

    CAS  Article  PubMed  Google Scholar 

  18. Feo TA, Resende MGC (1995) Greedy randomized adaptive search procedures. J Glob Optim 6(2):109–133

    Article  Google Scholar 

  19. Mizuno H et al (2010) Fine-scale detection of population-specific linkage disequilibrium using haplotype entropy in the human genome. BMC Genet 11(1):27

    Article  PubMed  Google Scholar 

  20. Vazquez A et al (2010) Chemosensitivity profiles identify polymorphisms in the p53 network genes 14-3-3tau and CD44 that affect sarcoma incidence and survival. Cancer Res 70(1): 172–180

    Google Scholar 

  21. Vazquez A et al (2008) The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 7(12):979–987

    CAS  Article  PubMed  Google Scholar 

  22. Feng Z et al (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102(23):8204–8209

    CAS  Article  PubMed  Google Scholar 

  23. Klinge CM (2001) Estrogen receptor interaction with estrogen response elements. Nucl Acids Res 29(14):2905–2919

    CAS  Article  PubMed  Google Scholar 

  24. Jerry DJ, Dunphy KA, Hagen MJ (2010) Estrogens, regulation of p53 and breast cancer risk: a balancing act. Cell Mol Life Sci 67(7): 1017–1023

    Google Scholar 

  25. Sangrajrang S et al (2009) Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women. Int J Cancer 125(4):837–843

    CAS  Article  PubMed  Google Scholar 

  26. Zhang L et al (2009) Association of genetic polymorphisms of ER-alpha and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women. Breast Cancer Res Treat 114(2):327–338

    CAS  Article  PubMed  Google Scholar 

  27. Setiawan VW et al (2009) Two estrogen-related variants in CYP19A1 and endometrial cancer risk: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium. Cancer Epidemiol Biomarkers Prev 18(1):242–247

    CAS  Article  PubMed  Google Scholar 

  28. Bertheau P et al (2008) TP53 status and response to chemotherapy in breast cancer. Pathobiology 75(2):132–139

    CAS  Article  PubMed  Google Scholar 

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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).

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