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Degree

Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology, 2006.

Abstract

Although BRCA1 and BRCA2 have been identified as the prototypes of the breast cancer suppressor genes, the genetic defects responsible for the majority of breast cancers remain to be revealed. Cancer cells silence tumor suppressor genes (TSGs) by the two-hit mechanism in which loss-of-function mutations and loss-of-heterozygousity (LOH) most frequently occur at the TSG loci. X-linked tumor suppressors are of great interest since one allele of these genes can be silenced by X-chromosome inactivation in females. The X-linked gene FoxP3 is a member of the forkhead-box/winged-helix transcription factor family. Germ-line mutations of FoxP3 in both male mice (scurfy) and man result in severe autoimmune disease with early lethality. Here we report that Foxp3(sf/+) heterozygous mice develop malignancies at a high rate, the majority being mammary carcinomas that have inactivated the wild-type Foxp3 allele by skewed X-inactivation while overexpressed two critical oncogenes, HER2/ErbB2 and Skp2. We also show that FoxP3 represses these two oncogenes and inhibits tumor growth. Furthermore, FOXP3 is expressed in normal human breast epithelial cells but is silenced in most human breast cancers. The widespread gene deletion and somatic mutations at the FOXP3 gene locus were demonstrated by screening a large panel of human breast cancer samples. To our knowledge, FOXP3 is the first X-linked breast cancer suppressor gene to be identified, and our data suggests that an interesting interplay between FOXP3 and oncogenes is involved in breast tumorigenesis.

Keywords

Breast Cancer; Tumor Suppressor gene; X Chromosome; FoxP3; HER2/ErbB2; SKP2

Advisor

Yang Liu

Pages

136p.

Document number: osu1150079443
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=osu1150079443

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