Hunting for Novel X-Linked Breast Cancer Suppressor Genes in Mouse and Human; Final rept. 15 Feb 2006-14 Feb 2007

摘要

A priori X-linked tumor suppressor genes would be of great interest as one allele of these genes might be silenced due to X-chromosome inactivation. The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germ-line mutations cause lethal autoimmune diseases in males. Serendipitously we observed that Foxp3sf/+ heterozygous mice developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and ErbB2 was over-expressed. Foxp3 bound and repressed the ErbB2 promoter. Deletion functionally significant somatic mutations and down-regulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2 over-expression regardless of the status of HER-2 amplification. In toto the data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.