TFoxP3 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

FOXP3 is inactivated in breast cancer cells by a number ofmechanisms, including somatic mutations, deletion, andepigenetic silencing. Because the mutation and deletion areusually heterozygous in the cancer samples, it is of interestto determine whether the gene can be induced for thepurpose of cancer therapy. Here, we report that anisomycin,a potent activator of activating transcription factor (ATF) 2,and c-Jun-NH2-kinase, induces expression of FoxP3 in bothnormal and malignant mammary epithelial cells. Theinduction is mediated by ATF2 and c-Jun. Targeted mutationof ATF2 abrogates both constitutive and inducible expressionof FoxP3 in normal epithelial cells. Both ATF2 and c-Juninteract with a novel enhancer in the intron 1 of the FoxP3locus. Moreover, shRNA silencing of ATF2 and FoxP3 revealsan important role of ATF2-FoxP3 pathway in the anisomycin-induced apoptosis of breast cancer cells. A low dose ofanisomycin was also remarkably effective in treating estab-lished mammary tumor in the mice. Our data showed thatFoxP3 can be reactivated for cancer therapy. [Cancer Res2009;69(14):5954–60]