| Antiestrogen treatment is often the therapy of choice for women with estrogen receptor-positive (ER+) breast cancer. Tamoxifen (TAM), one of the most widely used antiestrogens in breast cancer therapy, improves disease-free as well as overall survival in most ER+ breast cancer patients. The steroidal antiestrogen, ICI 182,780 (ICI), 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. 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 the deregulation of Bcl-2 expression is a critical step in developing antiestrogen resistance, but that these antiestrogen-resistant breast cancer cells are now more susceptible to cell death induced by Bcl-2 inhibitors.;We now report that baseline and antiestrogen treated expression of the anti-apoptotic proteins Bcl-2 and Bcl-w is increased in the ICI/TAM-resistant breast cancer cells, with deregulation of expression occurring at the level of transcription. We also observed that AP-1, a transcription factor with binding sites on the Bcl-2 promoter, is overexpressed in ICI treated resistant cells. After examining antiapoptotic Bcl-2 protein expression in a model of TAM only resistance, we found that there is no change in Bcl-2 or Bcl-w in the TAM-resistant MCF7/RR cell line as compared to MCF7 cells.;We also determined that the inhibition of Bcl-2 and Bcl-w increases ICI sensitivity in sensitive cells and restores ICI sensitivity in the resistant cells, with no effect seen following TAM treatment. However, in ICI-resistant cells we found that co-inhibiting Bcl-2 and Bcl-w increased both autophagy and necrosis, not apoptosis. We also found that inhibiting autophagy does not further decrease cell proliferation; however, there is a decrease in necrosis and an increase in apoptosis. Thus, we conclude that the altered expression of Bcl-2 family proteins may promote the development of acquired antiestrogen resistance by allowing breast cancer cells to evade cell death when undergoing antiestrogen treatment. |
