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.
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