Abstract
3659
Antiestrogen treatment is often the therapy of choice for women with estrogen receptor-positive (ER+) breast cancer. In most cases, the growth of these cancers is dependent on the hormone estrogen, and inhibiting the effects of estrogen by treating women with an antiestrogen is very successful. One of the most widely used antiestrogens has been Tamoxifen, which can improve disease-free as well as overall survival in ER+ breast cancer patients. Unfortunately, resistance to antiestrogen therapy is a common problem and an overwhelming concern in the clinic. In preliminary studies our data suggests that the estrogen-dependent prosurvival proto-oncogene Bcl-2 is playing a key role in the resistant cells’ response to an antiestrogen. We have found that breast cancer cells with acquired antiestrogen resistance exhibit significantly higher expression levels of Bcl-2 than antiestrogen sensitive breast cancer cells. The goal of this study is to discover how regulation of Bcl-2 is altered in antiestrogen-resistant breast cancer cell lines. Our hypothesis is that deregulation of Bcl-2 expression is a critical step in the development of antiestrogen resistance. To test this hypothesis, we used four antiestrogen-sensitive and -resistant cell lines. We examined the level of Bcl-2 protein expression by Western blot as well as the transcriptional activity of Bcl-2 by transfecting the cells with luciferase promoter-reporter constructs. Bcl-2 promoter activity and protein levels are relatively high in the MCF-7 cell line that is sensitive to antiestrogens, but these are significantly lower in the LCC1 cell line (antiestrogen sensitive and estrogen independent for growth). The LCC9 cell line, which is derived from LCC1 cells, is both tamoxifen and ICI 182,780 resistant. Its Bcl-2 promoter activity and protein levels are significantly increased relative to the LCC1 cells. We are currently investigating how estrogen and antiestrogens may regulated Bcl-2 transcription by the examining the activity of both the P1 and P2 promoters of Bcl-2. In conclusion our data suggests that there is a direct correlation between Bcl-2 basal promoter activity and protein levels in antiestrogen-sensitive and -resistant cell lines. In future studies we will identify specific changes in Bcl-2 transcription and regulation by looking at Bcl-2 mRNA levels and by identifying transcription factors that may play a role in antiestrogen resistance
[Proc Amer Assoc Cancer Res, Volume 47, 2006]