Targeting estrogen to kill ER-positive and ER-negative breast cancer

The current fashion of using long-term antihormonal therapies for the treatment and prevention of breast cancer has been remarkably successful over the past 20 years but this strategy has consequences for the development of drug resistance in remaining tumor tissue. Although estrogen is considered to be a survival signal that causes increased breast cancer cell replication, the study of drug resistance to antihormonal therapies has revealed an unanticipated new biology of estrogen action. Long-term antihormonal therapy eventually results in either tamoxifen or raloxifene (selective estrogen receptor modulators [SERMs]) stimulated growth and tumors are also stimulated to grow with estrogen. This is why aromatase inhibitors are effective treatments after the development of SERM resistance once the SERM is stopped. Long-term estrogen deprivation initially causes a cessation of breast tumor cell growth but eventually cells grow out that remain ER-positive but grow spontaneously. Estrogen deprivation with SERMs or aromatase inhibitors for more than 5 years causes a remarkable switching of the estrogen signaling pathway [1]. Instead of being a survival signal, physiologic concentrations of estrogen now cause apoptosis and tumor cell death. This knowledge provides an opportunity to test the hypothesis that low-dose estrogen therapy following exhaustive antihormonal therapy could be used as a successful treatment for patients. Studies are in place to evaluate the mechanism of action of estrogen-induced apoptosis so that a new target can be discovered to develop a novel apoptotic drug group. The ER-negative breast cancer cell is the ultimate hormone-resistant cell. Reintroduction of an active ER gene re-sensitizes the cells to estrogen that now causes blockade of the cell cycle [2] and apoptosis if cell survival signaling is also blocked. These data suggest that a universal target could be identified using the estrogen receptor mediated mechanism that will permit the broad application of new anti-apoptotic medicines.