While it is widely accepted that the risk of developing breast cancer is directly related to one's lifetime exposure to estrogen, the precise role of estrogen in the initiation and progression of breast cancer has yet to be determined. We reported that estrogens downregulate the expression of the transcription factor Hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1), and HEXIM1, in turn, inhibits Estrogen Receptor (ER?) transcriptional activity. Our mechanistic studies suggest that HEXIM1 mediates a novel link between ER? and transcription elongation factor, cyclin T1. HEXIM1 inhibits the co-recruitment of ER? and cyclin T1 to the promoter region of ER? target genes. As a result, HEXIM1 prevents ER?-mediated transcriptional elongation in breast epithelial cells. A mouse model created in my laboratory whereby HEXIM1 overexpression was targeted to the mammary gland produced results consistent with HEXIM1 inhibition of cyclin D1 and mammary epithelial cell proliferation via repression of cyclin T1. While the vast majority of the literature on HEXIM1 mechanism of action has focused on its functional interaction with the elongation machinery, our studies support biological actions of HEXIM1 that are not dependent upon its ability to interact with cyclin T1. This conclusion is based on our studies using a mutant HEXIM11-312 protein that is able to inhibit cyclin T1. We now report that this mutant HEXIM1 protein is able to actively promote mammary tumorigenesis. Together our results indicate that HEXIM1 plays a critical role in estrogen-regulated breast cancer. Based upon our findings, we hypothesize that modulation by HEXIM1 of estrogen-regulated transcription plays an important role in mammary gland development/tumorigenesis. The main specific aims of the proposed studies are to determine: (1) Does the recruitment of HEXIM1 and the inhibition of ER?-regulated transcriptional elongation play critical roles in the repressive effects of tamoxifen-liganded ER?? (2) What is the relative contribution of ER?-HEXIM1 functional interaction to HEXIM1 regulated transcriptional networks? (3) Will inactivation of HEXIM1 lead to mammary tumorigenesis that can be modulated by estrogens?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092440-10
Application #
8239921
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Woodhouse, Elizabeth
Project Start
2001-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$290,758
Indirect Cost
$96,758
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Yeh, I-Ju; Song, Kyung; Wittmann, Bryan M et al. (2014) HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens. Biochem J 462:315-27
Zhong, Bo; Lama, Rati; Ketchart, Wannarasmi et al. (2014) Lead optimization of HMBA to develop potent HEXIM1 inducers. Bioorg Med Chem Lett 24:1410-3
Ketchart, W; Smith, K M; Krupka, T et al. (2013) Inhibition of metastasis by HEXIM1 through effects on cell invasion and angiogenesis. Oncogene 32:3829-39
Montano, Monica M; Desjardins, Candida L; Doughman, Yong Qui et al. (2013) Inducible re-expression of HEXIM1 causes physiological cardiac hypertrophy in the adult mouse. Cardiovasc Res 99:74-82
Yeh, I-Ju; Ogba, Ndiya; Bensigner, Heather et al. (2013) HEXIM1 down-regulates hypoxia-inducible factor-1* protein stability. Biochem J 456:195-204
Ketchart, W; Ogba, N; Kresak, A et al. (2011) HEXIM1 is a critical determinant of the response to tamoxifen. Oncogene 30:3563-9
Smith, Kerri M; Ketchart, Wannarasmi; Zhou, Xiang et al. (2011) Determination of hexamethylene bisacetamide, an antineoplastic compound, in mouse and human plasma by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 879:2206-12
Krishnamurthy, N; Ngam, C R; Berdis, A J et al. (2011) The exonuclease activity of hPMC2 is required for transcriptional regulation of the QR gene and repair of estrogen-induced abasic sites. Oncogene 30:4731-9
Ogba, N; Doughman, Y Q; Chaplin, L J et al. (2010) HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland. Oncogene 29:3639-49
Vickerman, Mary B; Keith, Patricia A; McKay, Terri L et al. (2009) VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks. Anat Rec (Hoboken) 292:320-32

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