The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Abstract

The successful use of high dose synthetic estrogens to treat post-menopausal 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) for 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, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. 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 (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with 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 five year gap is necessary after menopause to permit the selection of estrogen deprived breast cancer cell populations to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around the menopause encourages ER positive tumor cell growth, 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 support the clinical findings for the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long term antihormonal adjuvant therapy, and the results of ERT and ERT plus progestin in the Women’s Health Initiative for women over the age of 60. Principles have emerged to understand and apply physiologic estrogen therapy appropriately by targeting the correct patient populations.

Integration of Downstream Signals of Insulin-like Growth Factor-1 Receptor by Endoplasmic Reticulum Stress for Estrogen-Induced Growth or Apoptosis in Breast Cancer Cells

“…This new biology of E 2 -induced apoptosis has been successfully used in clinical trials (7, 8). In the past, we have focused on the investigation of apoptosis-related signal pathways, genes, and cytoplasm organelles’ stress induced by E 2 in long-term E 2 -deprived breast cancer cells (5, 12, 13, 14, 23).…”

“…However, acquired resistance to anti-estrogen therapies is still a challenge in the clinic. Laboratory findings that re-transplantation of tamoxifen-stimulated tumors into successive generations of athymic mice over 5 years results in the selection of a resistant tumor cell population that is killed by physiological levels of E 2 (2, 3), has resulted in the new biology of E 2 -induced apoptosis (4–7). Indeed, E 2 -induced apoptosis has been used successfully to treat breast cancer after the failure of AI therapy (8) and to explain the action of E 2 replacement therapy for postmenopausal women in their 60s having a lower incidence of breast cancer and mortality (9, 10).…”

NJK14013, a novel synthetic estrogen receptor-α agonist, exhibits estrogen receptor-independent, tumor cell-specific cytotoxicity

“…Hormone replacement therapy (HRP) was once widely used to ameliorate and prevent postmenopausal symptoms, including VMS and osteoporosis. However, its use has drastically declined since a report by the Women's Health Initiative (WHI) showed that HRP increases the risk of strokes, breast cancer, and pulmonary embolism (16)(17)(18)(19) (2,20). Recently, another estrogenic SERM, ospemifene, was approved by the US Food and Drug Administration for dyspareunia associated with vulvar and vaginal atrophy and menopause (21).…”

The 4Ps of Breast Cancer Chemoprevention: Putting Proven Principles into Practice

“…This is a demonstration of the consistent “carry over protective effect” of long term estrogen deprivation (LTED) therapies used to treat or prevent breast cancer (4). Since tamoxifen is not itself a cytotoxic agent, it is proposed that breast tumor cells with acquired resistance to LTED do not grow with estrogen but are killed by a woman’s own estrogen that induces apoptosis (5). …”