Evolution of estrogen action in breast cancer: From culprit to killer

The rise of tamoxifen as the first targeted therapy for breast cancer that started in 1972 and the subsequent decades of research into hormonal therapy have saved the lives of hundreds of thousands of women. Continuing mechanistic studies elucidated the ability of tamoxifen to act as a selective estrogen receptor modulator (SERM), maintaining or building bone density and lowering circulating cholesterol, while reducing the risk of cancer in the breast. This pharmacologic research gave rise to raloxifene and a whole new drug group, the SERMs. However, through the study of antihormone resistance a surprise was in store with the discovery of a new biology of physiologic estrogen action. After years of adapting to an estrogen deficient environment, due to estrogen deprivation or antiestrogen treatment, breast cancer cells reconfigure their response to the former trophic factor, estrogen, into a potent apoptotic trigger. Estrogen can be used to treat antihormone resistant metastatic breast cancer, but more importantly, the finding of the Women's Health Initiative (WHI) that conjugated equine estrogen alone can reduce mortality by a significant decrease in total cancer and can be explained by the new apoptotic biology of estrogen.