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.

The discovery of 17β-estradiol (E2)–induced apoptosis has clinical relevance. Mechanistically, E2 over activates nuclear estrogen receptor α that results in stress responses. The unfolded protein response (UPR) is initiated by E2 in the endoplasmic reticulum after hours of treatment in endocrine-resistant breast cancer cells, thereby activating three UPR sensors—PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) with different functions. Specifically, PERK plays a critical role in induction of apoptosis whereas IRE1α and ATF6 are involved in the endoplasmic reticulum stress-associated degradation (ERAD) of PI3K/Akt/mTOR pathways. In addition to attenuating protein translation, PERK increases the DNA-binding activity of NF-κB and subsequent TNFα expression. In addition, PERK communicates with the mitochondria to regulate oxidative stress at mitochondria-associated endoplasmic reticulum membranes (MAM). Furthermore, PERK is a component enriched in MAMs that interacts with multifunctional MAM-tethering proteins and integrally modulates the exchange of metabolites such as lipids, reactive oxygen species (ROS), and Ca2+ at contact sites. MAMs are also critical sites for the initiation of autophagy to remove defective organelles and misfolded proteins through specific regulatory proteins. Thus, PERK conveys signals from nucleus to these membrane-structured organelles that form an interconnected network to regulate E2-induced apoptosis. Herein, we address the mechanistic progress on how PERK acts as a multifunctional molecule to commit E2 to inducing apoptosis in endocrine-resistant breast cancer.

Stress responses are critical for estrogen (E₂)-induced apoptosis in E₂-deprived breast cancer cells. Nuclear factor-kappa B (NF-κB) is an important therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E₂ activates NF-κB to participate in stress-associated apoptosis in E₂-deprived breast cancer cells is unknown. Here, we demonstrated that E₂ differentially modulates NF-κB activity according to treatment time. E₂ initially has significant potential to suppress NF-κB activation; it completely blocks tumor necrosis factor alpha (TNFα)-induced activation of NF-κB. We found that E₂ preferentially and constantly enhances the expression of the adipogenic transcription factor CCAAT/enhancer binding protein beta (C/EBPβ), which is responsible for the suppression of NF-κB activation by E₂ in MCF-7:5C cells. Interestingly, NF-κB p65 DNA-binding activity is increased when E₂ is administered for 48 h, leading to the induction of TNFα and associated apoptosis. Blocking the nuclear translocation of NF-κB can completely prevent the induction of TNFα and apoptosis induced by E₂. Further examination revealed that protein kinase RNA-like endoplasmic reticulum kinase (PERK), a stress sensor of unfolded protein response (UPR), plays an essential role in the late activation of NF-κB by E₂. This modulation between PERK and NF-κB is mainly mediated by a stress responsive transcription factor, transducer and activator of transcription 3 (STAT3), independently of the classic canonical IκBα signaling pathway. Thus, inhibition of PERK kinase activity completely blocks the DNA binding of both STAT3 and NF-κB, thereby preventing induction of NF-κB-dependent genes and E₂-induced apoptosis. All of these findings suggest that PERK is a key regulator to convey stress signals from the endoplasmic reticulum to the nucleus and illustrate a crucial role for the novel PERK/STAT3/NF-κB/TNFα axis in E₂-induced apoptosis in E₂-deprived breast cancer cells.

Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment of breast cancer inevitably occurs, but unexpectedly low-dose estrogen can cause regression of breast cancer and increase disease-free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here, we describe modulation of the estrogen receptor (ER) liganded with antiestrogens (endoxifen and 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE), ethoxytriphenylethylene (EtOXTPE), on estrogen-induced apoptosis in LTED breast cancer cells. Our results show that the angular TPE estrogen (EtOXTPE) is able to induce the ER-mediated apoptosis only at a later time compared with planar estradiol in these cells. Using real-time polymerase chain reaction, chromatin immunoprecipitation, western blotting, molecular modeling, and X-ray crystallography techniques, we report novel conformations of the ER complex with an angular estrogen EtOXTPE and endoxifen. We propose that alteration of the conformation of the ER complexes, with changes in coactivator binding, governs estrogen-induced apoptosis through the protein kinase regulated by RNA-like endoplasmic reticulum kinase sensor system to trigger an unfolded protein response.

Cancer Drug Resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc. Both clinical and experimental aspects of drug resistance in cancer are included.

While rare compared to female breast cancer the incidence of male breast cancer (MBC) has increased in the last few decades. Without comprehensive epidemiological studies, the explanation for the increased incidence of MBC can only be speculated. Nevertheless, one of the most worrying global public health issues is the exponential rise in the number of overweight and obese people, especially in the developed world. Although obesity is not considered an established risk factor for MBC, studies have shown increased incidence among obese individuals. With this observation in mind, this article highlights the correlation between the increased incidence of MBC and the current trends in obesity as a growing problem in the 21st century, including how this may impact treatment. With MBC becoming more prominent we put forward the notion that, not only is obesity a risk factor for MBC, but that increasing obesity trends are a contributing factor to its increased incidence.