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. Author manuscript; available in PMC: 2015 Jul 13.
Published in final edited form as: Discov Med. 2010 Oct;10(53):322–328.

FOXP3 as X-linked Tumor Suppressor

Lizhong Wang 1, Runhua Liu 1, Mark Ribick 1, Pan Zheng 1,2, Yang Liu 1,3
PMCID: PMC4500105  NIHMSID: NIHMS536835  PMID: 21034673

Abstract

The FOXP3 gene was initially identified because its mutation caused lethal autoimmune diseases in mouse and human. Mice with heterozygous mutation of Foxp3 succumb to mammary tumor spontaneously, while those with prostate-specific deletion 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 were usually inactivated by mutations in both alleles, X-linked FOXP3 mutations in cancer samples are usually heterozygous. The unique inheritance suggests a new approach to reactivation FOXP3 for cancer therapy.

Keywords: FOXP3, Tumor suppressor gene, Human cancer, X-linked gene, X-chromosome inactivation

Introduction

Extensive X-chromosomal loss of heterozygosity (LOH) is identified in breast cancer cell lines and primary cancers (Sirchia et al., 2005; Wang et al., 1990). Approximately 40% ovarian cancer also exhibit LOH at the X chromosome (Buekers et al., 2000; Chenevix-Trench et al., 1997; Cheng et al., 1996; Choi et al., 1997; Dodson et al., 1993; Edelson et al., 1998; Osborne and Leech, 1994; Yang-Feng et al., 1993; Yang-Feng et al., 1992). In addition, a role for X-linked genes that control the susceptibility to human prostate cancer has also been suggested by several studies. Thus, in hereditary prostate cancer, X-linked (HPCX) region at Xq27-q28 has been proposed as a prostate cancer susceptibility locus (Lange et al., 1999; Peters et al., 2001; Stephan et al., 2002; Xu et al., 1998; Yaspan et al., 2008). Recently, a haplotype at Xq27.2 (Xu et al., 1998; Yaspan et al., 2008) and common sequence variant at Xp11.22 (Gudmundsson et al., 2008) have been shown to confer susceptibility to prostate cancer, suggesting that two loci may have X-linked prostate cancer susceptibility genes. Moreover, linkage analyses showed that a locus at Xq27 is associated with susceptibility to testicular germ-cell tumor (Crockford et al., 2006; Rapley et al., 2000), suggesting the existence of potential X-linked susceptibility genes. However, no specific X-linked tumor suppressor genes have been identified until recently. This review focuses on FOXP3, one of the two X-linked tumor suppressors genes identified in 2007.

Evidence for FOXP3 as an X-linked Tumor Suppressor Gene in breast cancer

The X-linked gene FOXP3 at Xp11.23 is a member of the forkhead-box/winged-helix transcription factor family. It was identified during positional cloning of Scurfin, a gene responsible for X-linked autoimmune diseases in mice and humans (Bennett et al., 2001; Brunkow et al., 2001; Chatila et al., 2000; Wildin et al., 2001). FOXP3 protein localizes in the nucleus, and it functions as a sequence-specific transcription factor (Katoh et al.; Zuo et al., 2007b). FOXP3 is highly expressed in regulatory T cells and function as the master regulator during the development and function of regulatory T cells (Hori et al., 2003). In addition, FoxP3 is also expressed in epithelial cells of breast, prostate and lung (Chen et al., 2008).

Serendipitously, we observed that mice with a spontaneous mutation of the X-linked FoxP3 developed mammary tumors at a high rate. As evidence for wide-spread FOXP3 inactivation, nuclear FOXP3 is expressed in normal human breast epithelial cells but is lost in 80% of human breast cancers (Zuo et al., 2007b). The significance of FOXP3 as an X-linked tumor suppressor gene in humans is supported by the prevalence of somatic mutations (36%), gene deletion (13%) and lack of nuclear FOXP3 present in the majority of breast cancer samples (Zuo et al., 2007b). Interestingly, an overwhelming majority of the mutations are heterozygous and the deletion of the gene is heterozygous in all cases. These data reaffirm the notion that a single-hit is sufficient to inactivate X-linked genes.

FOXP3 inhibits breast tumor growth through directly repressing the transcription activity of two oncogenes (HER2 and SKP2) while inducing the transcription activity of tumor suppressor gene p21 (Liu et al., 2009; Zuo et al., 2007a; Zuo et al., 2007b) (Fig. 1). Therefore, FOXP3 is an X-linked breast cancer suppressor gene in both mice and humans.

Fig. 1.

Fig. 1

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FOXP3 suppresses prostate cancer and breast cancer by inducing tumor suppressor genes while repressing oncogenes. The genes indicated are all direct target for FOXP3 and their regulations are essential for growth inhibition by FOXP3. Gene array analysis indicates that FOXP3 induction causes alteration of 1805 genes, using ≥ 150% (1285 genes) or ≤ 66% (520 genes) of the levels found in control cells as cut-off. The raw data for microarray analyses have been deposited to MIAExpress (accession no. E-MTAB-73).

FOXP3 as X-linked tumor suppressor gene in prostate cancer

Recent epidemiological studies have suggested two loci at Xp11.22 (Gudmundsson et al., 2008) and Xq27-28 (Xu et al., 1998; Yaspan et al., 2008) are associated with the susceptibility to prostate cancer, but the genes in these regions have not been identified. Because FOXP3 resides near the Xp11.22 region and reveals significant linkage disequilibrium (LD) between them, these results raised an interesting possibility that the FOXP3 locus may contributed to X-linked prostate cancer susceptibility.

We analyzed the FOXP3 expression in a large panel of human prostate cancer samples. As expected, nuclear FOXP3 is expressed in normal human prostate epithelial cells but is lost in approximately 70% of human prostate cancers. FOXP3 is frequently inactivated in prostate cancer samples by deletion (14%) and somatic mutation (25%) (Wang et al., 2009). The significance of such inactivation is confirmed by strong growth inhibition of prostate cancer cell lines by FOXP3 (Wang et al., 2009). Importantly, prostate-specific ablation of the FoxP3 in the mouse caused early onset of prostate hyperplasia and prostatic intraepithelial neoplasia (PIN) (Wang et al., 2009). Therefore, FOXP3 is also an X-linked tumor suppressor gene for prostate cancer. Functional analysis showed that FOXP3-mediated transcriptional repression of c-MYC is necessary to control c-MYC levels in normal prostate epithelial cells (Fig. 1) and that explains much of the widespread overexpression of MYC in prostate cancer (Wang et al., 2009).

FOXP3 and ovarian cancer

In ovarian cancer, FOXP3 was shown to be weakly or not expressed in ovarian cancer cells (Zhang and Sun). Transfection with FOXP3 inhibited cell proliferation, decreased cell migration, and reduced cell invasion (Zhang and Sun). FOXP3 up-regulated cells showed decreased expression of Ki-67 and cyclin-dependent kinases. FOXP3 can inhibit cell migration and invasion by reducing the expression of matrix metalloproteinase-2 and urokinase-type plasminogen activator in ovarian cancer cells. These data suggested that up-regulation of FOXP3 could be a novel approach for inhibiting ovarian cancer progression.

Confusions on FOXP3 expression in cancer samples

Considerable confusion exists in literature regarding FOXP3 expression in human cancers. The confusion is due to at least two reasons. The first is whether cytoplasmic or nuclear FOXP3 is scored. Because FOXP3 is a transcription factor, we only consider nuclear FOXP3 as positive (Liu et al., 2009; Wang et al., 2009; Zuo et al., 2007a; Zuo et al., 2007b). Using this criteria, FOXP3+ tumor samples is usually less than 30%. On the other hand, if cytoplasmic FOXP3 is counted, then the % of FOXP3 samples were considerably higher. Thus, Karanikas et al analyzed the expression of FOXP3 in 25 tumor cell lines, including lung cancer, colon cancer, breast cancer, melanoma, erythroid leukemia, acute T-cell leukemia. In most cell lines, the authors reported both Foxp3 mRNA and its protein (Karanikas et al., 2008). Immunohistochemical staining of these cell line cytospins showed the predominant cytoplasmic expression of FOXP3 in melanoma (GERL), colon (HCA 2.6) and breast cancer (MCF7) cell lines and both cytoplasmic and nuclear expression in lung cancer (GILI) and T lymphoblastic leukemia (JURKAT). Likewise, Hinz et al reported that FOXP3 expression was detected in pancreatic cancers but most of them are cytoplasmic staining (Hinz et al., 2007). Without discriminating cellular localization, Merlo et al. reported a high rate of FOXP3 expression in breast cancer samples (Merlo et al., 2009). More recently, Ladoire et al revealed that FOXP3 in all HER2 positive breast cancer samples are only expressed in the cytoplasm (Ladoire et al.; Martin et al.). Our analyses of somatic FOXP3 mutants indicate the majority of the missense mutations disrupted their nuclear localization (Wang et al., 2009) (and unpublished observations). More importantly, the cytoplasmic localization is the best correlates of lacking growth inhibition (Wang et al., 2009) (and our unpublished observations). We and others have reported alternative splicing form, which also should disrupt localization of FOXP3 (Ebert et al., 2008; Katoh et al.; Krejsgaard et al., 2008; Zhang and Sun; Zuo et al., 2007b).

The second reason for confusion is use of different anti-FOXP3 antibodies in immunohistochemical staining. A recent study showed that FOXP3 immunohistochemistry on formalin-fixed paraffin-embedded tissue has poor correlation between monoclonal antibodies 236A/E7 and mAbcam 22510 in sections of different organs (Woo et al., 2008). We have also compared specificity and sensitivity of several anti-FOXP3 mAbs, including 236A/E7, hFOXY, eBio7979 and FJK-16s for immunohistochemistry staining in both human normal epithelial cells and cancer cells (Wang et al., 2009) and confirmed specificity of 236A/E7 using cells with FOXP3 silencing (Wang et al., 2009).

Reactivation of FOXP3 for cancer therapy

One of the most difficult challenges in cancer therapy is to restore the function of inactivated tumor suppressors. Autosomal tumor suppressor genes are often deleted and/or mutated in both alleles. It is therefore difficult to repair what is genetically broken. On the other hand, mutation of X-linked tumor suppressor genes, such as FOXP3 and WTX, are often heterozygous in female cancer cells (Rivera et al., 2007; Zuo et al., 2007b). Since one allele of X-linked tumor suppressor gene has not undergone selection during carcinogenesis, it may be possible to reactivate the WT allele for cancer therapy. Indeed, anisomycin treatment induced FOXP3 expression in both mouse and human breast cancer cell lines (Liu et al., 2009b). Such induction resulted in increased apoptosis of cancer cells and reduced growth of established mouse mammary tumors (Liu et al., 2009b). This observation raises the intriguing possibility of restoring FOXP3 function. This information will benefit the development of a novel therapeutic strategy for breast cancer therapy.

Obviously, given the physiological function of X-inactivation, global reactivation of X-linked genes may have serious side effects. Two lines of observations may mitigate this concern. First, global analysis of X-inactivation suggests that an additional 10% of X-linked genes show variable patterns of inactivation and are expressed from some inactive X chromosomes in human (Carrel and Willard, 2005). Therefore, less than precise X-inactivation is tolerated in human. Second, since DNA methylation, XIST and histone hypoacetylation work in concert to maintain inactivation of X-linked genes (Cohen and Lee, 2002; Heard and Disteche, 2006; Pageau et al., 2007; Plath et al., 2002), loss of DNA methylation and Xist on X chromosome, which is observed in breast cancer samples (Richardson et al., 2006), should reduce the steps needed to reactivate X-linked tumor suppressor genes and thus provides a rationale to selectively reactivate FOXP3 in cancer tissue.

Acknowledgments

This word was supported by funding from the National Institutes of Health and the Department of Defense.

Footnotes

Conflict of Interest Statement

The authors declare no conflict of interest.

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