FOXP3 Is an X-Linked Breast Cancer Suppressor Gene and an Important Repressor of the HER-2/ErbB2 Oncogene

Abstract

The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germline mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that female mice heterozygous for the "scurfin" mutation of the Foxp3 gene (Foxp3(sf/+)) developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and HER-2/ErbB2 was overexpressed. Foxp3 bound and repressed the HER-2/ErbB2 promoter. Deletion, functionally significant somatic mutations, and downregulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2/ErbB2 overexpression, regardless of the status of HER-2 amplification. Our data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.

Human FOXP3 and cancer

“…A nuclear localization of FOXP3 was also reported for most human normal and cancer cells expressing this factor (Zuo et al, 2007b;Ebert et al, 2008;Wang et al, 2009). However, a predominant cytoplasmic FOXP3 labeling was reported for human pancreatic cancer cells (Hinz et al, 2007).…”

“…C-MYC is involved with ras in prostate carcinogenesis (Thompson et al, 1989) and is overexpressed in 80% of the prostate cancer samples. A significant correlation was observed between FOXP3 downregulation and HER-2 and SKP2 or cMYC overexpression in breast and prostate cancer cells (Zuo et al, 2007a(Zuo et al, , 2007bWang et al, 2009).…”

“…However, due to its location on the X chromosome, it is also an appropriate target for a single hit process that will suppress its expression or function, release the repressed oncogenes and initiate transformation (Figure 2). Interestingly, transfection of the full-length FOXP3 cDNA in human breast or prostate cancer cell lines repressed colony formation, thus further demonstrating a tumor suppressor role for FOXP3 (Zuo et al, 2007b;Wang et al, 2009).…”

“…The levels and isoforms of the FOXP3 transcripts were analyzed in a panel of primary normal human mammary epithelial cells, and in malignant breast cancer cell lines (Zuo et al, 2007b). FOXP3 transcripts with the same two isoforms as found in Treg were observed in noncancerous epithelial cells.…”

Is FOXP3 a bona fide marker for human regulatory T cells?

“…Furthermore, the mechanisms determining the role of FOXP3 as negative or positive regulators are still elusive. Interestingly, it has been recently reported that FOXP3 is expressed in mammary epithelial cells and acts as transcriptional repressor of oncogenes [34,35]. This opens new perspectives on the role of FOXP3 in regulating fundamental biological functions of cells, such as cell cycle and apoptosis.…”