FOXP3 Is an X-Linked Tumor Suppressor

Abstract

Many breast cancers occur in conjunction with overexpression of the ERBB2 oncogene (also known as HER-2 or Neu ). Although gene amplification can lead to ERBB2 overexpression, some human cancers overexpress ERBB2 even without gene amplification. Zuo et al . noticed that a large percentage of older female mice heterozygous for a mutation in the Foxp3 gene ( Foxp3 sf/+ ) developed spontaneous cancers; about 60% of these were mammary carcinomas. Further, these mice showed increased susceptibility to developing mammary cancer in response to treatment with the carcinogen DMBA together with progesterone. Analysis of normal mammary epithelial tissue and mammary cancer cells microdissected from heterozygous mice revealed that the wild-type allele of Foxp3 was expressed in the former and silenced in the latter, which also showed increased ErbB2 expression. Chromatin immunoprecipitation analysis indicated that a Foxp3 fusion protein, which decreased ErbB2 expression when transfected into a mouse mammary tumor cell line (TSA), bound the ErbB2 promoter, and mutational analysis of reporter activity combined with electrophoretic mobility shift assay indicated that Fox3p binding was required for repression of ErbB2 . FOXP3 silencing with siRNA in normal human mammary epithelial cells led to an increase in ERBB2 expression, whereas induction of FOXP3 expression in a breast cancer cell line with ERBB2 gene amplification decreased ErbB2 abundance at the cell surface. Defects in FOXP3 were observed in human breast cancer cell lines and breast cancer tissues, and the presence of such defects showed a correlation with increased abundance of ErbB2. Intriguingly, transfection of Foxp3 into breast cancer cell lines reduced their in vitro and in vivo growth. Thus, the authors conclude that FOXP3 is a tumor suppressor that regulates ERBB2 . Medema and Burgering discuss the implications of X chromosome inactivation with regard to X-linked tumor suppressors and the possibility that the role of Foxp3 in development of regulatory T cells may contribute to its tumor suppressor activity. T. Zuo, L. Wang, C. Morrison, X. Chang, H. Zhang, W. Li, Y. Liu, Y. Wang, X. Liu, M. W. Y. Chan, J.-Q. Liu, R. Love, C.-g. Liu, V. Godfrey, R. Shen, T. H.-M. Huang, T. Yang, B. K. Park, C.-Y. Wang, P. Zheng, Y. Liu, FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129 , 1275-1286 (2007). [PubMed] R. H. Medema, B. M. Th. Burgering, The X factor: Skewing X inactivation towards cancer. Cell 129 , 1253-1254 (2007). [PubMed]