Breast cancer is a heterogeneous disease which arises due to complex molecular changes. Among various molecular changes, Polycomb group (PcG) proteins are known to be aberrantly expressed during breast cancer progression. In particular, BMI1 and EZH2 are overexpressed in breast cancer cells. The exact role of BMI1 in breast cancer progression is not very well understood. A better understanding of oncogenic activity of BMI1 and its regulation is necessary to define its oncogenic role in breast cancer. The long-term objectives of this proposal are- identify molecular targets of BMI1, study signaling pathways that regulate BMI1 expression, and explore the role of BMI1 in drug resistance in breast cancer cells and breast cancer patients.
In aim 1, we will identify molecular mechanisms which regulate expression of BMI1. In particular, we will study posttranslational regulation of BMI1 in normal human mammary epithelial cells and breast cancer cells. We will also identify novel signaling pathways that are involved in BMI1 proteolysis induced by genotoxic drugs in breast cancer cells.
In aim 2, we plan to identify potential oncogenic mutations in BMI1 oncogene, which may make it more stable and potent, and study the oncogenic role of mutant BMI1 proteins in breast cancer.
In aim 3, we plan to study the oncogenicity of wild type and mutant BMI1 proteins using mouse xenograft studies and identify potential breast cancer-related targets of BMI1 using microarray analysis.
In aim 4, we plan to study the role of BMI1 in chemoresistance in breast cancer patients. Successful outcome of the proposed studies will help in understanding the role of BMI1-regulated and BMI1 regulating pathways which could be targeted for breast cancer therapy. A clear understanding of signaling pathways regulating BMI1 expression will also help in developing breast cancer therapies that target BMI1 and BMI1 containing PcG complexes which are dysregulated in breast cancer.

Public Health Relevance

The proposed studies will help understand the role of Polycomb Group protein BMI1 in cancer development, progression and treatment. These studies will help in developing breast cancer therapies that could target BMI1 expression to halt breast cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094150-10
Application #
8540346
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mietz, Judy
Project Start
2001-12-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$248,063
Indirect Cost
$89,556
Name
George Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Cho, Joon-Ho; Dimri, Manjari; Dimri, Goberdhan P (2013) A positive feedback loop regulates the expression of polycomb group protein BMI1 via WNT signaling pathway. J Biol Chem 288:3406-18
Itahana, Koji; Itahana, Yoko; Dimri, Goberdhan P (2013) Colorimetric detection of senescence-associated * galactosidase. Methods Mol Biol 965:143-56
Sahasrabuddhe, Anagh A; Dimri, Manjari; Bommi, Prashant V et al. (2011) ?TrCP regulates BMI1 protein turnover via ubiquitination and degradation. Cell Cycle 10:1322-30
Yadav, Ajay K; Sahasrabuddhe, Anagh A; Dimri, Manjari et al. (2010) Deletion analysis of BMI1 oncoprotein identifies its negative regulatory domain. Mol Cancer 9:158
Bommi, Prashant V; Dimri, Manjari; Sahasrabuddhe, Anagh A et al. (2010) The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors. Cell Cycle 9:2663-73
Zhang, Xiao-Wei; Sheng, Ya-Ping; Li, Qian et al. (2010) BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer. Mol Cancer 9:40
Dimri, Manjari; Bommi, Prashant V; Sahasrabuddhe, Anagh A et al. (2010) Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells. Carcinogenesis 31:489-95
Hoenerhoff, M J; Chu, I; Barkan, D et al. (2009) BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 28:3022-32
Xu, Chuan-Rui; Lee, Susie; Ho, Coral et al. (2009) Bmi1 functions as an oncogene independent of Ink4A/Arf repression in hepatic carcinogenesis. Mol Cancer Res 7:1937-45
Dimri, Goberdhan P (2009) c-Myc and telomerase activation. Cell Cycle 8:3075-6

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