Heterozygous Genetic Variations of FOXP3 in X p11.23 Elevate Breast Cancer Risk in Chinese Population via Skewed X ‐Chromosome Inactivation

FOXP3 (forkhead box P 3: also known as IPEX , XPID ) is not only a hallmark of immunosuppressive regulatory T cells ( T regs), but also an X ‐linked breast cancer suppressor gene expressed in tumor cells. A two‐stage investigation was conducted in individuals from northern, southern and eastern C hina. Individuals carrying a FOXP3 rs2294021 CT genotype showed about 1.5‐fold increased risk of breast cancer compared with TT carriers. In a related biochemical assay, the rs2294021 C allele was found to significantly enhance transcription activity, leading to higher m RNA levels of FOXP3 compared with T allele. Moreover, the number of T regs and its corresponding interleukin‐10 ( IL ‐10) secretion were elevated whereas the proliferation of antitumor T cells was decreased in the C ‐allele carriers. The breast cancer oncogenes H er‐2/ E rb B 2 and S kp2 were also found to be significantly inhibited in C ‐allele carriers. Moreover, skewed X ‐chromosome inactivation ( SXCI ) analysis showed that rs2294021 CT carriers with SXCI showed higher risk than the homozygous carriers and CT carriers without SXCI , suggesting a possible interaction between the rs2294021 CT genotype and SXCI . Taken together, these findings indicate that the rs2294021 CT genotype may increase an individual's susceptibility to breast cancer by breaking the balance between T reg‐mediated immune tolerance and FOXP3 ‐controlled tumor‐suppressive effect.