IPEX Syndrome, FOXP3 and Cancer

Abstract

In this review, we introduce the IPEX syndrome and its relationship with germline mutations of the FOXP3 gene. We then describe the multiple functional roles of FOXP3 in regulatory T cells and epithelial cells as well as in IPEX syndrome and tumor progression. Potential mechanisms of FOXP3 inactivation and transcriptional regulation are discussed with recent advances. Finally, we point out current issues and a potential FOXP3-mediated therapeutic strategy as well as the reactivation of FOXP3 in patients with IPEX syndrome and cancer.

Keywords: Cancer; FOXP3; IPEX; Syndrome; Tumor suppressors.

Figure 1

Functional domains and mutations in coding region of the human FOXP3 gene. FOXP3 transcript consists of 12 exons and the open reading frame is from exons 2 to 12. There are 4 potential functional domains (hollow boxes). Black starts indicate germline mutations identified from IPEX patients. Black arrows indicate somatic mutations from breast cancer patients, and solid triangles indicate somatic mutations from prostate cancer patients.

Figure 2

Functional signaling pathways in the context of FOXP3. FOXP3 is highly expressed in Treg cells, but also detected in both epithelial and non-epithelial cells, including many cancer cells. Several hundred target genes of the FOXP3 have been identified in both Treg cells and epithelial cells. TGFβ: transforming growth factor β; TCR: T cell receptor; CTLA4: cytotoxic T-lymphocyte-associated protein 4; IL2: interleukin 2; IL2Ra: IL2 receptor a; IL7Ra: IL7 receptor a; LATS2: large tumor suppressor kinase 2; ATF2: ATF2 activating transcription factor 2; HER2: v-erb-b2 erythroblastic leukemia viral oncogene homolog 2; SKP2: S-phase kinase-associated protein 2; CDKs: cyclin-dependent kinases; mTOR: mammalian target of rapamycin; NFκB: nuclear factor κB; MMP2: matrix metalloproteinase 2; uPA: urokinase-type plasminogen activator; BRCA1: breast cancer 1, early onset; CXCR4: chemokine (C-XC motif) receptor 4.