In the current studies we aim to directly determine the role of ErbB-2 and cyclin D1 in cellular proliferation and transformation in prostate cancer cells. Both ErbB-2 and cyclin D1 are frequently over-expressed in prostate, breast and colon cancer. Our laboratory has contributed to the current understanding that the cyclin D1 gene is transcriptionally activated by a number of growth factors and oncogenes, including oncogenic ErbB-2. We and others have shown that the abundance of cyclin D1 is rate-limiting in progression through the G1 phase of the cell-cycle and is required for transformation by Ras and ErbB-2 in fibroblast assays. The central hypothesis of these studies is that ErbB-2 regulation of cyclin D1 plays a critical role in promoting prostate cellular proliferation. We propose to test this hypothesis directly using transgenic mice. Determining the role of ErbB-2 and cyclin D1 in prostate cancer progression and determining the mechanisms by which cyclin D1 is regulated and its effects on prostate cell proliferation will provide important insights into the mechanisms governing prostate tumor growth. Thought transgenic mice have been made which over-express aggressive oncogenes in the prostate and lead to Prostate cancer, the experiments described here focus on two gene products (ErbB-2 and cyclin D-1) implicated in human Prostate cancer. Furthermore, these transgenic mice may prove extremely valuable in the testing of proposed Prostate cancer therapeutics.
Aim 1. To determine the role of ErbB-2 in prostate cell proliferation in vivo. Transgenic mice containing a wild type human ErbB-2 receptor under the control of the Probasin promoter have been made and will be analyzed and a mutant form of the human ErbB-2 receptor, which contains a 16 amino acid in frame exon deletion found in human tumors, under the control of the Probasin promoter will be analyzed. Our laboratory has considerable experience in the generation of transgenic mice.
This Aim will determine role of ErbB-2 over expression in prostate cellular proliferation and the role of ErbB-2 in enhancing prostate cellular transformation and tumorigenesis.
Aim 2. To determine the role of cyclin D1 in prostate cell proliferation in vivo. Transgenic mice are being generated over expressing a flat-tagged cyclin D1 cDNA under the control of the Probasin promoter.
This Aim will determine the role of cyclin D1 over expression in Prostate cellular proliferation/or tumor formation and the role of cyclin D1 in enhancing prostate cellular transformation. As cyclin D1 over-expression has been shown to compliment the transforming capacity of certain oncogenes and to be necessary for transformation capacity by ErbB-2, the Probasin- ErbB-2 mice will be crossed with the Probasin-cyclin D1 mice and the rate of tumor onset and progression will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG020337-01
Application #
6440109
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Bellino, Francis
Project Start
2002-04-01
Project End
2002-08-31
Budget Start
2002-04-01
Budget End
2002-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$36,769
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Vissapragada, Sarada; Ghosh, Anup; Ringer, Lymor et al. (2010) Dietary n-3 polyunsaturated fatty acids fail to reduce prostate tumorigenesis in the PB-ErbB-2 x Pten(+/-) preclinical mouse model. Cell Cycle 9:1824-9
Hulit, James; Lee, Richard J; Li, Zhiping et al. (2006) p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-catenin signaling. Cancer Res 66:8529-41
Sakamaki, Toshiyuki; Casimiro, Mathew C; Ju, Xiaoming et al. (2006) Cyclin D1 determines mitochondrial function in vivo. Mol Cell Biol 26:5449-69
Lewis, Joan S; Thomas, T J; Pestell, Richard G et al. (2005) Differential effects of 16alpha-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells. J Mol Endocrinol 34:91-105
Song, D H; Kaufman, J C; Borodyansky, L et al. (2005) Gastrin stabilises beta-catenin protein in mouse colorectal cancer cells. Br J Cancer 92:1581-7
Wang, Chenguang; Fan, Saijun; Li, Zhiping et al. (2005) Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity. Cancer Res 65:6557-67
Lewis, Joan S; Vijayanathan, Veena; Thomas, T J et al. (2005) Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. Oncol Res 15:113-28
Giampuzzi, Monia; Oleggini, Roberta; Albanese, Chris et al. (2005) beta-catenin signaling and regulation of cyclin D1 promoter in NRK-49F cells transformed by down-regulation of the tumor suppressor lysyl oxidase. Biochim Biophys Acta 1745:370-81
D'Amico, Mark; Wu, Kongming; Fu, Maofu et al. (2004) The inhibitor of cyclin-dependent kinase 4a/alternative reading frame (INK4a/ARF) locus encoded proteins p16INK4a and p19ARF repress cyclin D1 transcription through distinct cis elements. Cancer Res 64:4122-30
Hulit, James; Wang, Chenguang; Li, Zhiping et al. (2004) Cyclin D1 genetic heterozygosity regulates colonic epithelial cell differentiation and tumor number in ApcMin mice. Mol Cell Biol 24:7598-611

Showing the most recent 10 out of 15 publications