FoxP3 Functions as a Novel Breast Cancer Suppressor Gene Through Cooperation with NFAT

摘要

FoxP3 is among the newest members of the forkhead winged helix family and a gene responsible for X-linked autoimmune diseases IPEX (Immune dysregulation, polyendopathy, enterophathy, X-linked) in mice and humans. In our analysis of the immune functions of mice heterozygous for the FoxP3 mutation, we observed a high rate of spontaneous mammary cancer. Meanwhile, a recent study indicated that mice with a targeted mutation of NFAT also developed spontaneous mammary cancers. In our study, we found the FoxP3 gene was down-regulated in the mammary cancer tissues. Meantime, over-expression of FoxP3 in a variety of breast cancer cells resulted in a substantial inhibition of their growth. Furthermore, FoxP3 inhibited the transcription of ErbB2, the major oncogene for breast cancer, by targeting and repressing the ErbB2 promoter and the growth inhibition was completely reversed by constitutive expression of the ErbB2 gene. Our data revealed that FoxP3 is an important breast cancer suppressor gene in mice and humans and NFAT4 also repressed Erb2 transcription by measuring ErbB2 reporter activity, suggesting NFAT4 may serve as a repressor for ErbB2/Her-2 promoter. NFAT4 was found in a complex with FoxP3, indicating they may functionally play important roles together. Our further analysis also found decrease of NFAT4 expression in some of mice breast cancer samples. In summary, our data suggest FoxP3 and NFAT are important breast cancer suppressor genes in the mouse model.