Department of Medicine, Division of Medical Oncology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
Breast Cancer Res Treat. 2011 Feb;125(3):861-8. doi: 10.1007/s10549-010-1062-1. Epub 2010 Jul 25.
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.
TSC1 与 TSC2 形成复合物协同作用，抑制 mTOR，mTOR 是一个新兴的治疗靶点，也是促进细胞生长和细胞周期进展的已知促进因子。mTOR 通路的异常表达或功能的改变，可能导致肿瘤发生。与正常乳腺上皮相比，侵袭性乳腺癌中 TSC1 和 TSC2 的表达降低。由于调节基因中的单核苷酸多态性（SNP）与乳腺癌的风险和发病年龄有关，因此对 TSC1 和 TSC2 的 SNP 进行了系统的 SNP 关联研究，以探讨它们与乳腺癌临床特征的关系。在健康志愿者中，对这两个基因的多个位点进行基因分型，构建 TSC1 和 TSC2 单体型。使用基于 SNP 与 NCI-60 细胞系药物反应的关联和基于单体型频率的选择偏差证据的生物信息学方法，选择 SNP 进行进一步研究。对 1137 名乳腺癌女性的基因组 DNA 进行了 5 个 TSC1 和 1 个 TSC2 位点的基因分型。这项研究发现，对于 TSC1 rs7874234，TT 变异携带者的雌激素受体阳性（ER+）但不是 ER-、导管癌的诊断年龄晚 9 年（P = 0.0049）。没有其他 SNP 位点与诊断年龄相关，也没有其他乳腺癌表型相关。推测 TSC1 rs7874234 在 ER+乳腺癌中具有功能，因为 T 等位基因，但不是 C 等位基因，可能创建一个雌激素受体元件（ERE）位点，导致 TSC1 转录增加，随后抑制 mTOR。
