The goal of cancer therapeutics is to destroy the cancer cell selectively without killing the patient. To achieve the goal, two interrelated strategies can be applied: critical survival targets can be identified and blocked to prevent tumor growth or a critical promoter of carcinogenesis can be identified and blocked to prevent the development of a tumor. Each of these strategies have been successfully applied to breast cancer treatment by exploiting knowledge of the estrogen receptor (ER) signal transduction system to target and block cancer cell survival. (1). As a result, 400,000 women are alive today because of the appropriate application of long-term tamoxifen (antiestrogen) therapy and tamoxifen is the first medicine to be approved to reduce the incidence of breast cancer in high risk women (2,3). The therapeutic advance, through translational research, has encouraged multiple new approaches to the long-term treatment and prevention of breast cancer to improve current standards of patient care. Tamoxifen is not an antiestrogen in all estrogen target tissues in the body but rather a selective ER modulator (SERM). The new class of drugs has already successfully targeted the ER to treat osteoporosis by increasing bone density (estrogen-like effect) but simultaneously reducing the incidence of breast cancer (antiestrogen effect) (4). The SERM raloxifene is currently being evaluated as a second medicine to reduce the incidence of breast cancer in high risk women. The Study of Tamoxifen and Raloxifene (STAR) has completed recruitment (19,000+ volunteers) and the analysis of results will be available in 2006. The success of SERMs as multifunctional medicines has resulted in an enhanced interest in developing new tissue and ER subtype specific SERMs (5,6) or designer estrogens (7). This is especially true in the wake of reports that combined estrogen progestin hormone replacement therapy, used by tens of millions of women throughout the world, provides no overall health benefits (8–11). New designer estrogen could provide important selective benefits in women’s health. An alternate therapeutic strategy, specifically targeted to the ER signal transduction pathways in breast cancer, is to use aromatase inhibitors to deplete estrogen from postmenopausal women. There is no doubt that superior results can be obtained when compared to the old SERM tamoxifen (12,13) but the challenge will be to compare aromatase inhibitors to new SERMs for prevention. Overall, the breast cancer treatment trend over the past 30 years has gone from short courses (1 year) of additive hormone therapy in the final stages of disease (14) to perhaps indefinite antihormonal therapy in the earliest stages of the disease (15). The continuous antihormonal strategy, however, has consequences for the survival of breast cancer cells that unexpectedly exposes a vulnerability that again can be targeted to kill cancer cells through the ER. Exhaustive antihormonal therapy does not cause apoptosis and cell death but causes accumulated survival medicines that permits ER mediated growth as an expression of drug resistance (16). However, stopping the antihormonal therapy and reintroducing low concentrations of estrogen results in rapid collapse of survival mechanisms with the initiation of apoptosis (17–19). This intriguing finding raises the possibility that an ER mediated apoptotic trigger could be discovered to target a new generation of therapeutic agents for clinical evaluation.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]