Previous work in our laboratory has demonstrated that the paclitaxel induced initial phase of apoptosis in a variety of cell lines including MCF-7 breast cancer cells and BR ovarian cells is mediated through a Ras/Rac/Ask1/JNKK/JNK signal transduction pathway. However, the second phase of paclitaxel action is not prevented by blockade of this pathway. Recent studies on MCF-7 cells and a variety of other cell types suggests that estrogens can inhibit apoptosis, more specifically, data indicates a possible interaction between paclitaxel and estrogens in regulating apoptosis in breast cancer cells. Several studies also suggest that antiestrogens have apoptotic effects in ER positive breast Ca cells. We have accumulated preliminary evidence confirming an anti-apoptotic role for estrogens in MCF-7 cells. However, the mechanisms of estrogen action as an anti-apoptotic agent or their potential interactions with pro-apoptotic agents such as paclitaxel are totally unknown. Elucidations of these interactions is particularly significant since estrogens and microtubule interfering agents (MIAs) such as paclitaxel have clinically established roles in promotion and therapy of breast and ovarian cancer respectively. We propose that estrogens can act as anti-apoptotic agents because of their ability to regulate the Ras/Rac-JNK pathway and the Cdk/cyclin/Cdk inhibitor activity in breast and ovarian cancer cells. We have proposed the following Specific Aims to test this broad hypothesis.
Specific Aim 1 : Determine the role of Cdks in the apoptotic action of paclitaxel in MCF-7 and BR and BG1 (ovarian) cancer cells with the intention of elucidating the role of the cell cycle, if any, in paclitaxel action.
Specific Aim 2 : Analyze the putative interactions between paclitaxel and estradiol in regulating apoptosis in the above cell lines. Experiments will be designed to elucidate interaction of estrogens with the Ras/Rac/JNKK/JNK/AP1 pathway activated by paclitaxel.
Specific Aim 3 : Given the fact that estrogens can regulate the activity of several genes which can modulate apoptosis, we will determine potential role of c-myc, Bc12, p53, p300/CBP Akt in the anti apoptotic effects of estradiol using overexpression of wild type and dominant negative (DN) versions of the genes of interest.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA084048-01
Application #
6032882
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Fu, Yali
Project Start
2000-02-01
Project End
2003-12-31
Budget Start
2000-02-01
Budget End
2000-12-31
Support Year
1
Fiscal Year
2000
Total Cost
$237,293
Indirect Cost
Name
University of Tennessee Knoxville
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Cekanova, Maria; Fernando, Romaine I; Siriwardhana, Nalin et al. (2015) BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion. Exp Cell Res 331:1-10
Henley, D; Isbill, M; Fernando, R et al. (2007) Paclitaxel induced apoptosis in breast cancer cells requires cell cycle transit but not Cdc2 activity. Cancer Chemother Pharmacol 59:235-49
Foster, James S; Fernando, Romaine I; Ishida, Noriko et al. (2003) Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK pathway. J Biol Chem 278:41355-66
Ahamed, Shamila; Foster, James S; Bukovsky, Antonin et al. (2002) Removal of Cdk inhibitors through both sequestration and downregulation in zearalenone-treated MCF-7 breast cancer cells. Mol Carcinog 34:45-58
Ahamed, S; Foster, J S; Bukovsky, A et al. (2001) Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7 cells. Mol Carcinog 30:88-98
Foster, J S; Henley, D C; Ahamed, S et al. (2001) Estrogens and cell-cycle regulation in breast cancer. Trends Endocrinol Metab 12:320-7
Foster, J S; Henley, D C; Bukovsky, A et al. (2001) Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Mol Cell Biol 21:794-810