50943

FOXP3

AIID|DIETER|IPEX|JM2|PIDX|XPID;forkhead box P3;FOXP3;forkhead box P3

FOXP3delta7|forkhead box protein P3|immune dysregulation, polyendocrinopathy, enteropathy, X-linked|immunodeficiency, polyendocrinopathy, enteropathy, X-linked|scurfin

Xp11.23

protein-coding

Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here, we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly overexpressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Because the male has only one X chromosome, our data represent a paradigm of "single genetic hit" inactivation-mediated carcinogenesis.

The FOXP3 gene was initially identified because its mutation caused lethal autoimmune diseases in mice and humans. Mice with heterozygous mutations of FoxP3 (mouse version of the FOXP3 gene) succumb to mammary tumors spontaneously, while those with prostate-specific deletions develop prostate intraepithelial neoplasia. Somatic mutations, deletion, and epigenetic inactivation of FOXP3 are widespread among human breast and prostate cancers. Unlike autosomal tumor suppressor genes that are usually inactivated by mutations in both alleles, X-linked FOXP3 mutations in cancer samples are usually heterozygous, with the wildtype allele selectively inactivated in cancer. This skewed X-inactivation suggests a new approach to reactivation of FOXP3 for cancer therapy.

Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer.

The FoxP3 (forkhead box P3) gene is an X-linked gene that is submitted to inactivation. It is an essential transcription factor in CD4(+)CD25(+)FoxP3 regulatory T cells, which are therapeutic targets in disseminated cutaneous melanoma. Moreover, FoxP3 is an important tumor suppressor gene in carcinomas and has putative cancer suppressor gene function in cutaneous melanoma as well. Therefore understanding the structure and function of the FoxP3 gene is crucial to gaining insight into the biology of melanoma to better develop immunotherapeutics and future therapeutic strategies.

OBJECTIVE: To explore the expression of CD4(+), IL-17 and Foxp3 in non-small cell lung cancer (NSCLC) and their relationship with microvessel density (MVD). METHODS: The expressions of CD4(+), IL-17, Foxp3, CD31 and CD34 in the cancer tissues of 102 NSCLC cases were detected by immunohistochemisty. The relationship among the expressions of CD4(+), IL-17, Foxp3 and MVD was analyzed. The count data were analyzed using chi(2) test. The measurement data were analyzed using single-factor analysis of variance, and significance level alpha = 0.05. RESULTS: Among the factors affecting CD31 expression, there was a statistically significant difference between the strong positive Foxp3 expression (++) and negative (-) and positive expressions (+) in the NSCLC cancer tissues (P < 0.05), and between the expressions in stage I and III cancer tissues (P < 0.05). Among the factors affecting CD34 expression, there was a significant difference between positive IL-7 expression (+) and strong positive IL-7 expression (++) (P < 0.05), between negative Foxp3 expression (-) and strong positive Foxp3 expression (++) (P < 0.05), and between the CD34 expressions in stage I and III and between those in stage II and III NSCLC cancer tissues (P < 0.05). CONCLUSIONS: CD4, IL-17and Foxp3 may be involved in the tumor suppression caused by host immune response, and are related with the NSCLC invasion and metastasis.