Tamoxifen (TAM), one of the most widely used antiestrogens in breast cancer therapy, has demonstrated the ability to improve disease-free as well as overall survival in most ER+ breast cancer patients. The steroidal antiestrogen ICI 182,780 (ICI; Fulvestrant) is a pure antagonist of the ER and is often effective as a second-line treatment for women who do not respond to TAM. Unfortunately, the development of resistance to both of these antiestrogen therapies is an overwhelming concern in the clinic. It is widely known that defects in the apoptotic pathway can lead to drug resistance, and both TAM and ICI can induce apoptosis in breast cancer cells. However, the precise mechanism by which impaired apoptosis contributes to antiestrogen resistance remains unknown. We and others have demonstrated that antiestrogens can regulate apoptosis by altering the expression of BCL2 family members, but the effects of TAM and ICI are not always consistent. Therefore, we hypothesize that BCL2 family members play distinct roles in antiestrogen-resistant breast cancer that are determined by the type of antiestrogen to which the cells display resistance. To test this hypothesis, we used two antiestrogen-sensitive and -resistant breast cancer cell line pairs: ICI-resistant MCF7/LCC9 cells and their sensitive controls MCF7/LCC1, and the TAM-resistant MCF7/RR cells and their sensitive controls MCF7. Baseline expression of the anti-apoptotic proteins Bcl-2 and Bcl-w is increased in the ICI-resistant LCC9 cells as compared to LCC1. However, there is no change in these anti-apoptotic BCL2 family genes in the TAM-resistant MCF7/RR cell line as compared to MCF7 cells. In contrast TAM-resistant MCF7/RR cells express significantly lower levels of the pro-apoptotic proteins Bax and Bad relative to MCF7 cells, while there is no significant difference in the expression of these molecules between ICI-resistant LCC9 cells and -sensitive LCC1 cells. Finally, we have also shown that the regulation of BCL2 family members\#8217; expression by TAM and ICI is altered in the resistant breast cancer cells. Bcl-2 expression is not reduced by ICI in the resistant LCC9 cells as compared to LCC1, while Bax and Bad induction by TAM is delayed in MCF7/RR cells relative to MCF7. In conclusion our data suggest that anti-apoptotic BCL2 family members play a role in ICI resistance and pro-apoptotic family members play a role in TAM resistance. Our data also suggest that altering Bcl-2 expression may restore antiestrogen sensitivity in cell lines resistant to both TAM and ICI. In future studies we will further identify specific changes in Bcl-2 family member transcription and regulation by identifying transcription factors that may play a role in antiestrogen resistance.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3266.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009