Polymorphisms In The FOXP3and EpCAM Gene And Breast Cancer Susceptibility In Chinese Populations

Part I affect of heterozygous variations of FOXP3on breast cancerrisk via skewed X-chromosome inactivationAs a transcription factor, FOXP3is not only a well known hallmark of immunesuppressive T regulatory cells (Tregs), but also an X-linked breast cancer suppressorgene expressed in tumor cell itself. Tregs are the major cell type mediating tumorimmunity suppression regulated by FOXP3expression. However, expression of Foxp3in breast cancer has been reported to suppress cancer cell growth. Recently, Zuo et al.reported that heterozygous FOXP3mutation leads to spontaneous development ofbreast cancer. Our study aims to find out whether genetic polymorphisms in FOXP3areassociated with breast cancer susceptibility and how the polymorphisms affect cancerrisk. Two-stage investigation is conducted in subjects derived from Northern, Southernand Eastern China. Interestingly, our study shows about1.5-fold increased risk of breastcancer in subjects with FOXP3rs2294021CT genotype compared with those with thers2294021CC+TT genotype in a case-control study in Chinese women (adjusted oddsratio (OR)=1.49;95%CI=1.34-1.67). Functional relevance of this polymorphism wasexamined by biochemical assay. We found that rs2294021CC genotype can enhance thetranscription activity of foxp3compared with CT or TT genotypes(P<0.001) and foxp3expression in rs2294021CC carries was significantly higher than that in CT or TTcarriers in both breast cancer tissue (P<0.001) and healthy blood lymphocytes (P<0.001).Moreover, the content of Tregs was elevated (P=0.004), while the proliferation of T cellswas decreased (P<0.001for both CD4+and CD8+cells) in the rs2294021C allelecarriers. Moreover, skewed X chromosome inactivation (SXCI) analysis showed thatrs2294021CT carriers with SXCI yielded the greatest risk compared with thehomozygous carriers and CT carriers without SXCI, suggesting a possible interactioneffect between rs2294021CT genotype and SXCI. All these findings indicate that rs2294021CT genotype may increase individual's susceptibility to breast cancer bybreaking the balance between Tregs mediated immune tolerance and FOXP3controlledtumor suppression effect. Part II A non-synonymous polymorphism Thr115Met in the EpCAMgene is associated with an increased risk of breast cancer in ChinesepopulationAs a tumor-associated antigen and a surface marker of breast cancer stem cells(BCSCs), epithelial cell adhesion molecule (EpCAM) plays an important role in notonly cell adhesion, morphogenesis, metastases but also carcinogenesis. Anon-synonymous C/T polymorphism (rs1126497) in exon3of EpCAM causes atransition of115amino acid from Met to Thr. Another polymorphism (A/G, rs1421) inthe3'UTR causes loss of has-miR-1183binding. A multiple independent case–controlanalysis was performed to assess the association between EpCAM genotypes and breastcancer risk. We observed that the variant EpCAM genotype (rs1126497CT, and TT)was associated with substantially increased risk of breast cancer. Genotyping a total of1643individuals with breast cancer and1818control subjects in Eastern and SouthernChinese populations showed that rs1126497CT? TT genotype had an odd ratio of1.40(95%confidence interval,1.16–1.57) for developing breast cancer compared with CCgenotype. The allele T increases the risk of breast cancer in a dose-dependent responsemanner (Ptrend<0.001). Moreover, compared to breast cancer patients carrying the CCgenotype, the EpCAM SNP rs1126497CT or TT carrier was significantly associatedwith early breast cancer onset (P=0.0023). However, no significant difference wasfound in genotype frequencies at the rs1421A/G site between cases and controls. Thesefindings suggest that M115T polymorphism in EpCAM may be a genetic modifier fordeveloping breast cancer.