The successful use of high-dose
synthetic estrogens to treat postmenopausal metastatic
breast cancer is the first effective 'chemical
therapy' proven in clinical trial to treat any
cancer. This review documents the clinical use of
estrogen for
breast cancer treatment or
estrogen replacement therapy (ERT) in postmenopausal hysterectomized women, which can either result in
breast cancer cell growth or
breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of
estrogen-induced apoptosis at the end of the 20th century. The key to triggering apoptosis with
estrogen is the selection of
breast cancer cell populations that are resistant to long-term
estrogen deprivation. However,
estrogen-independent growth occurs through trial and error. At the cellular level,
estrogen-induced apoptosis is dependent upon the presence of the
estrogen receptor (ER), which can be blocked by nonsteroidal or steroidal
antiestrogens. The shape of an estrogenic
ligand programs the conformation of the ER complex, which, in turn, can modulate
estrogen-induced apoptosis: class I planar
estrogens (e.g.,
estradiol) trigger apoptosis after 24 h, whereas class II angular
estrogens (e.g., bisphenol
triphenylethylene) delay the process until after 72 h. This contrasts with
paclitaxel, which causes G2 blockade with immediate apoptosis. The process is complete within 24 h.
Estrogen-induced apoptosis is modulated by
glucocorticoids and cSrc inhibitors, but the target mechanism for
estrogen action is genomic and not through a nongenomic pathway. The process is stepwise through the creation of endoplasmic reticulum stress and inflammatory responses, which then initiate an unfolded protein response. This, in turn, initiates apoptosis through the intrinsic pathway (mitochondrial) with the subsequent recruitment of the extrinsic pathway (
death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or
phytoestrogen supplements: a 5-year gap is necessary after menopause to permit the selection of
estrogen-deprived
breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with
estrogen around menopause encourages growth of ER-positive
tumor cells, as the cells are still dependent on
estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with
estrogen-induced apoptosis can be orchestrated in the laboratory in
estrogen-deprived breast
cancers now supports the clinical findings regarding the treatment of metastatic
breast cancer following
estrogen deprivation, decreases in mortality following long-term antihormonal adjuvant
therapy, and the results of treatment with ERT and ERT plus
progestin in the Women's Health Initiative for women over the age of 60. Principles have emerged for understanding and applying physiological
estrogen therapy appropriately by targeting the correct patient populations.