Breast cancer is a leading cause of cancer-related deaths in American women. Despite advances in early detection and treatment, mortality for those 20% of patients with recurrences and/or metastases is nearly 100%. Distinct sets of genes and proteins dictate progression from precursor lesions, to invasive carcinoma and finally to metastatic disease. Characterizing genes that regulate the growth and metastatic ability of breast cancer may identify novel biomarkers to help clinicians guide current treatments, and may offer novel targets for therapeutic intervention. We recently identified EZH2 (enhancer of Zeste homolog 2), a polycomb group protein (PcG), as being up-regulated in invasive and metastatic breast cancer. In Drosophila, PcG proteins have been shown to maintain gene expression programs during development by negatively regulating target loci including homeotic genes. The role of EZH2 in breast cancer has not been investigated. Our central hypothesis is that dysregulated expression of the PcG protein EZH2 promotes the growth and invasion of breast cancer by transcriptional silencing of specific target genes. Our long-term goal is to functionally characterize EZH2 and to elucidate its role as a novel biomarker of metastatic potential in breast cancer. The objective of this application is to begin to study the role of EZH2 in the development of breast cancer and delineate its clinical application.
The specific aims of this project are as follows: 1. To determine the clinical utility of EZH2 as a novel biomarker of aggressive breast cancer in a large group of invasive carcinomas of the breast with clinical and treatment information, 2. To determine the role of EZH2 in regulating neoplastic characteristics in vitro and in vivo by overexpressing or inhibiting EZH2 expression in immortalized human mammary epithelial cells and in breast cancer cells, and by developing transgenic mice overexpressing EZH2 in the mammary epithelium, and 3. To identify and characterize transcriptional target genes of EZH2 that play a role in breast cancer progression by performing transcriptome analysis on immortalized mammary epithelial cells overexpressing EZH2 and in tissues of invasive carcinomas with and without EZH2 overexpression. In summary, this proposal addresses the clinical utility and functional role of EZH2 in the regulation of breast cancer progression. ? ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107469-04
Application #
7339649
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mohla, Suresh
Project Start
2005-02-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$257,343
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Anwar, Talha; Arellano-Garcia, Caroline; Ropa, James et al. (2018) p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis. Nat Commun 9:2801
Martin, E E; Huang, W; Anwar, T et al. (2017) MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas. Oncogene 36:2275-2285
Gonzalez, Maria E; Martin, Emily E; Anwar, Talha et al. (2017) Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth. Cell Rep 18:1215-1228
Zhang, Yanhong; Liss, Adam L; Chung, Eugene et al. (2016) Stromal cells in phyllodes tumors of the breast are enriched for EZH2 and stem cell marker expression. Breast Cancer Res Treat 158:21-28
Huang, Wei; Martin, Emily E; Burman, Boris et al. (2016) The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. Oncotarget 7:25180-93
Kleer, Celina G (2016) Dual roles of CCN proteins in breast cancer progression. J Cell Commun Signal 10:217-222
Hertz, Daniel L; Henry, N Lynn; Kidwell, Kelley M et al. (2016) ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors. Physiol Genomics 48:688-98
Gonzalez-Guerrico, Anatilde M; Espinoza, Ingrid; Schroeder, Barbara et al. (2016) Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. Oncotarget 7:71151-71168
Toy, Kathy A; Valiathan, Rajeshwari R; Núñez, Fernando et al. (2015) Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat 150:9-18
Proctor, Erica; Kidwell, Kelley M; Jiagge, Evelyn et al. (2015) Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women. Ann Surg Oncol 22:3831-5

Showing the most recent 10 out of 63 publications