The (gene is an epithelial cell-intrinsic tumor suppressor for breast and prostate cancers. breast cancers (Liu Etoposide et al. 2009 Etoposide Zuo et al. 2007 Zuo et al. 2007 Moreover we recently found that also functions as a tumor suppressor in prostate cancer (Wang et al. 2009 Despite the importance of FOXP3 in mammary and prostate carcinogenesis pathways the signalling networks of FOXP3 in normal and/or malignant epithelial cells have not yet been fully elucidated. In this review we will focus on the function of the FOXP3 as a tumor suppressor in epithelial cells and discuss how its inactivation contributes to the malignant transformation of cells. We will also discuss how reactivation of FOXP3 in tumor samples may be explored for cancer therapy. 2 Functions and Pathologic Context FOXP3 is usually a member of the FOXP family which has at least four members FOXP1-4. All contain highly conserved c-terminal tetramerization domains composed of zinc-finger and leucine zipper domains and a DNA binding forkhead box domain name (Fig. 1) (Lopes et al. 2006 FOXP3 localizes in the nucleus and it functions as a sequence-specific transcription factor. The DNA binding forkhead MYO7A domain of FOXP3 binds to specific DNA sequences in gene promoters: 5′-RYMAAYA-3′ in which R=A/G Y=C/T M=A/C. Physique 1 A. Diagram of the human and its somatic mutations found among human breast and prostate cancers. ZF: zing finger domain. LZ: leucine-zipper domain. FKH: forkhead domain. B. Splice variants of the FOXP3 that are predominantly expressed in human cancers. … We observed that mice with germline mutations are substantially Etoposide more prone to developing mammary carcinomas either spontaneously or carcinogen-induced (Zuo et al. 2007 The role of the gene in the mammary carcinogenesis has been supported by several lines of evidence (Fig. 1). The gene is expressed in normal breast epithelia but is down-regulated in mammary cancer (Zuo et al. 2007 Ectopic expression of in variety of breast cancer cell lines resulted in cell cycle arrest; cessation of cell growth (Zuo et al. 2007 Moreover Foxp3 directly regulates transcription of and p21 (Liu et al. 2009 Zuo et al. 2007 Zuo et al. 2007 Furthermore our analyses of clinical human breast cancers also supported that FOXP3 plays an important role in mammary carcinogenesis (Fig. 1). Frequent chromosomal deletions and somatic mutations of the gene were detected in cancer samples (Zuo et al. 2007 By immunohistochemistry (IHC) onto tissue microarrays we found down-regulation of FOXP3 in cancer cells compared Etoposide to normal breast epithelia (Liu et al. 2009 Zuo et al. 2007 Zuo et al. 2007 Surprisingly a recent study showed the expression of FOXP3 in over 60% of breast cancer (Merlo et al. 2009 However this study included cancer cells expressing FOXP3 in its cytoplasmic form which may well be mutant FOXP3 (Wang et al. 2009 Etoposide The gene also plays an important role in prostate epithelia (Fig. 1) (Wang et al. 2009 Among human prostate cancers we found frequent chromosomal deletions somatic mutations and epigenetic silencing of the gene (Fig. 1) (Wang et al. 2009 Since the gene is located on the X chromosome a genetic/epigenetic single-hit results in inactivation of this gene in males. IHC revealed that FOXP3 expression was significantly down-regulated in cancer cells when compared to normal prostate glands (Wang et al. 2009 Moreover mice with prostate-specific ablations of gene plays an important role in the initial stage of prostatic carcinogenesis (Wang et al. 2009 Importantly we identified to be directly repressed by FOXP3 in prostate epithelia (Wang et al. 2009 A recent study reported that among 26 ovarian cancer samples the expression of the FOXP3 was significantly decreased as compared to normal ovarian epithelia (Zhang and Sun 2010 Another interesting aspect of FOXP3 abnormalities is that some types of cancers predominantly express splice variants of the FOXP3 protein. As shown in figure 1B among breast and ovarian cancers malignant melanomas and malignant T cells of Sezary syndrome specific splice variants of the FOXP3 such as Δ3 Δ3-4 Δ3/8 Etoposide and Δ8 were reported to be.