Breast cancer is a common malignancy that continues to take a devastating toll on American women. In majority of cases, breast cancer is a carcinoma arising from the transformation of mammary epithelial cells. Transformation is culmination of complex molecular genetic changes that occur in a normal cell, beginning with loss of normal growth control mechanisms. This loss of normal growth control mechanisms usually results in bypass of cellular senescence, and immortalization. The molecular genetic changes that result in senescence bypass and immortalization in human mammary epithelial cells (HMECs) are largely unknown. This proposal focuses on a candidate oncogene, Bmi-1 that has been shown to modulate senescence mechanisms in fibroblasts and cooperate with c-Myc in tumorigenesis. Recently, we observed that Bmi-1 can induce telomerase, cause significant replicative life-span extension and induce immortalization of HMECs. We also found that Bmi-1 is overexpressed in several breast cancer cell lines. Although, Bmi-1 is a known oncogene, its role in telomerase induction and breast cancer is not known. Our purpose to identify the molecular mechanisms of telomerase induction and immortalization by Bmi-1, and study its role in breast cancer. Using HMECs and wild type or mutant Bmi-1, first we will define the role of RING finger domain of Bmi-1 in immortalization and telomerase induction. Next, we will perform structural and functional analysis of telomerase promoter to identify the sequences required for telomerase induction in Bmi-1 overexpressing cells.
Our third aim i s to study the role of Bmi-1 interacting proteins, clone and identify novel Bmi-1 interacting proteins that may be involved in telomerase regulation. Next, we will study the role of Bmi-1 in ubiquitination and proteolysis of important cell cycle regulatory proteins and tumor suppressors. Finally, we will examine the oncogenic potential of Bmi-1 in-vitro using cell culture studies, and in-vivo using breast tumors at different stages to determine if Bmi-1 is overexpressed at a particular stage of breast cancer. These studies will define the role of Bmi-1 in breast cancer and determining the diagnostic and prognostic value of Bmi-1 expression as an early marker of breast cancer. These studies will also help us in understanding the mechanism of telomerase regulation and may yield new targets for telomerase inhibition.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094150-04
Application #
7117296
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
2003-09-17
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$264,202
Indirect Cost
Name
Northshore University Healthsystem
Department
Type
DUNS #
154538107
City
Evanston
State
IL
Country
United States
Zip Code
60201
Gergely, Joseph E; Dorsey, Armond E; Dimri, Goberdhan P et al. (2018) Timosaponin A-III inhibits oncogenic phenotype via regulation of PcG protein BMI1 in breast cancer cells. Mol Carcinog 57:831-841
Dimri, Manjari; Kang, Mingu; Dimri, Goberdhan P (2016) A miR-200c/141-BMI1 autoregulatory loop regulates oncogenic activity of BMI1 in cancer cells. Oncotarget 7:36220-36234
Cho, Joon-Ho; Dimri, Manjari; Dimri, Goberdhan P (2015) MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence. J Biol Chem 290:10555-67
Dimri, Manjari; Cho, Joon-Ho; Kang, Mingu et al. (2015) PLK1 inhibition down-regulates polycomb group protein BMI1 via modulation of the miR-200c/141 cluster. J Biol Chem 290:3033-44
Itahana, Koji; Itahana, Yoko; Dimri, Goberdhan P (2013) Colorimetric detection of senescence-associated ? galactosidase. Methods Mol Biol 965:143-56
Dimri, Manjari; Carroll, Jeremy D; Cho, Joon-Ho et al. (2013) microRNA-141 regulates BMI1 expression and induces senescence in human diploid fibroblasts. Cell Cycle 12:3537-46
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; Dimri, Goberdhan P (2012) pRb or its cousins: who controls the family business? Cell Cycle 11:1486
Dong, Qinghua; Oh, Ju-Eun; Chen, Wei et al. (2011) Radioprotective effects of Bmi-1 involve epigenetic silencing of oxidase genes and enhanced DNA repair in normal human keratinocytes. J Invest Dermatol 131:1216-25
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

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