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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Breast Neoplasms / genetics*
-
Breast Neoplasms / metabolism
-
Carcinoma / genetics*
-
Carcinoma / metabolism
-
Cell Line, Tumor
-
Chromosomes, Human, X / genetics
-
Down-Regulation / genetics
-
Female
-
Forkhead Transcription Factors / genetics*
-
Gene Expression Regulation, Neoplastic / genetics
-
Genes, Tumor Suppressor / physiology*
-
Genes, X-Linked / genetics*
-
Genes, erbB-2 / genetics*
-
Humans
-
Mammary Neoplasms, Experimental / genetics
-
Mammary Neoplasms, Experimental / metabolism
-
Mice
-
Mice, Inbred BALB C
-
Mice, Mutant Strains
-
Mutation / genetics
-
Promoter Regions, Genetic / genetics
-
Receptor, ErbB-2 / genetics
-
Receptor, ErbB-2 / metabolism
-
Tumor Suppressor Proteins / genetics
-
X Chromosome Inactivation / genetics
Substances
-
FOXP3 protein, human
-
Forkhead Transcription Factors
-
Tumor Suppressor Proteins
-
ERBB2 protein, human
-
Receptor, ErbB-2