Although the prototypes of breast cancer suppressor genes, BRCA1 and BRCA2, have been identified, the genetic defects responsible for the majority of breast cancer remain elusive. In addition, essentially all cancer suppressor genes identified are autosomal. X-linked tumor suppressors are of great interest as one allele of these genes can be silenced by X-chromosome inactivation in women. The X-linked FoxP3 is a member of the forkhead/winged helix transcription factor family. Mutations of FoxP3 in both mice (FoxP3sf) and man result in severe autoimmune disease with early lethality. We have recently made a surprising observation that FoxP3sf/+ mice develop cancer at a high rate. The majority of the cancers are mammary carcinomas that have silenced FoxP3 but have over-expressed ErbB2. The overall goal of the project is to build on this exciting preliminary study, to reveal the significance of FOXP3 as a cancer suppressor and to understand the mechanisms by which FoxP3 control breast cancer development in the mouse and in humans. We will continue our effort to study the significance of FoxP3-mediated repression of HER-2/ErbB2 suppression in the mouse model of breast cancer. In addition to HER-2/Neu, our preliminary data also suggest Skp2 and CD24 as novel FoxP3 targets. Their relevance in mammary cancer formation will be tested in vitro 2-D and 2-D culture as well as in vivo in transgenic and knock out models. In addition, we will take a global approach to identify target genes regulated by the FOXP3 protein. Furthermore, we have found widespread down- regulation of the FOXP3 gene among human breast cancer samples. We will test the hypothesis that the two alleles of the FOXP3 locus are silenced by loss of heterozygocity (LOH) in conjunction with X-chromosomal inactivation. In those samples that we have failed to detect mutation or LOH, we will test the possibility that bi-allelic epigenetic mechanisms may be involved in silencing the FOXP3 locus. Finally, we will determine expression of HER-2, SKP2, CD24 and other potential FOXP3 targets among the human breast cancer samples in order to establish a spectrum of mechanisms by which FOXP3 controls breast cancer development. Our proposed studies will not only have the potential for establishing FOXP3 as an important breast cancer suppressor gene but also provide a genetic mechanism for the abnormal expression of the major breast cancer oncogene, HER-2, in humans as well as a molecular mechanism for a major therapeutic modality. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA120901-01A2
Application #
7322626
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yassin, Rihab R,
Project Start
2007-09-01
Project End
2011-07-31
Budget Start
2007-09-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$310,612
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Katoh, Hiroto; Zheng, Pan; Liu, Yang (2013) FOXP3: genetic and epigenetic implications for autoimmunity. J Autoimmun 41:72-8
Katoh, Hiroto; Qin, Zhaohui S; Liu, Runhua et al. (2011) FOXP3 orchestrates H4K16 acetylation and H3K4 trimethylation for activation of multiple genes by recruiting MOF and causing displacement of PLU-1. Mol Cell 44:770-84
Li, Weiquan; Wang, Lizhong; Katoh, Hiroto et al. (2011) Identification of a tumor suppressor relay between the FOXP3 and the Hippo pathways in breast and prostate cancers. Cancer Res 71:2162-71
Katoh, Hiroto; Zheng, Pan; Liu, Yang (2010) Signalling through FOXP3 as an X-linked tumor suppressor. Int J Biochem Cell Biol 42:1784-7
Liu, Yang; Wang, Lizhong; Zheng, Pan (2010) X-linked tumor suppressors: perplexing inheritance, a unique therapeutic opportunity. Trends Genet 26:260-5
Liu, Yan; Wang, Yin; Li, Weiquan et al. (2009) Activating transcription factor 2 and c-Jun-mediated induction of FoxP3 for experimental therapy of mammary tumor in the mouse. Cancer Res 69:5954-60
Wang, Lizhong; Liu, Runhua; Li, Weiquan et al. (2009) Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 16:336-46
Liu, Runhua; Wang, Lizhong; Chen, Guoyun et al. (2009) FOXP3 up-regulates p21 expression by site-specific inhibition of histone deacetylase 2/histone deacetylase 4 association to the locus. Cancer Res 69:2252-9
Chen, Guo-Yun; Chen, Chong; Wang, Lizhong et al. (2008) Cutting edge: Broad expression of the FoxP3 locus in epithelial cells: a caution against early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells. J Immunol 180:5163-6