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Journal of Molecular Endocrinology Jan 2017About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates... (Review)
Review
About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.
Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Estrogen Antagonists; Estrogen Receptor alpha; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Models, Molecular; Molecular Conformation; Molecular Structure; Mutation; Protein Binding; Protein Processing, Post-Translational; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Structure-Activity Relationship; Treatment Outcome
PubMed: 27729460
DOI: 10.1530/JME-16-0024 -
Trends in Endocrinology and Metabolism:... Aug 2010Estrogen and its receptors are implicated in the promotion and prevention of various cancers. Although the uterine cervix is highly responsive to estrogen, the role of... (Review)
Review
Estrogen and its receptors are implicated in the promotion and prevention of various cancers. Although the uterine cervix is highly responsive to estrogen, the role of estrogen in cervical cancer, which is strongly associated with human papillomavirus (HPV) infections, is poorly understood. Recent studies in HPV transgenic mouse models provide evidence that estrogen and its nuclear receptor promote cervical cancer in combination with HPV oncogenes. Although epidemiological studies further support this hypothesis, there is little experimental data assessing the hormonal responsiveness of human cervical cancers. If these cancers are dependent on estrogen, then drugs targeting estrogen and its receptors could be effective in treating and/or preventing cervical cancer, the second leading cause of death by cancer among women worldwide.
Topics: Alphapapillomavirus; Animals; Estrogen Antagonists; Estrogen Receptor alpha; Estrogens; Female; Genes, Viral; Humans; Oncogenes; Papillomavirus Infections; Risk Factors; Selective Estrogen Receptor Modulators; Uterine Cervical Neoplasms
PubMed: 20456973
DOI: 10.1016/j.tem.2010.03.005 -
Endocrinology Dec 2021The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and... (Review)
Review
The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. In phase 1/2 clinical studies, the efficacy of Z-endoxifen, the active isomer of endoxifen, was evaluated in patients with endocrine-refractory metastatic breast cancer as well as in patients with gynecologic, desmoid, and hormone-receptor positive solid tumors, and demonstrated substantial oral bioavailability and promising antitumor activity. Apart from its potent anticancer effects, Z-endoxifen appears to result in similar or even greater bone agonistic effects while resulting in little or no endometrial proliferative effects compared with tamoxifen. In this review, we summarize the preclinical and clinical studies evaluating endoxifen in the context of breast and other solid tumors, the potential benefits of endoxifen in bone, as well as its emerging role as an antimanic agent in bipolar disorder. In total, the summarized body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications.
Topics: Animals; Bone and Bones; Breast Neoplasms; Cell Proliferation; Estrogen Antagonists; Female; Humans; Molecular Targeted Therapy; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen
PubMed: 34480554
DOI: 10.1210/endocr/bqab191 -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2012There are substantial experimental, epidemiological and clinical evidences that show that breast cancer pathology is influenced by endogenous estrogens. This knowledge... (Review)
Review
There are substantial experimental, epidemiological and clinical evidences that show that breast cancer pathology is influenced by endogenous estrogens. This knowledge is the foundation upon which endocrine deprivation therapy has been developed as a major modality for the management of breast cancer. Tamoxifen, which functions as a competitive partial agonist-inhibitor of estrogen at its receptor, has been widely used for more than three decades for adjuvant endocrine treatment in breast cancer. Currently, other effective drugs for endocrine therapy include raloxifene, different aromatase inhibitors (particularly third-generation agents) and luteinizing hormone-releasing hormone agonists. In recent years, a growing body of evidence suggests that these drugs can also act as immune modulators by altering the function of various leukocytes and the release of different cytokines. Moreover, there is evidence that anti-estrogens may prove to be beneficial in the treatment or prevention of some autoimmune diseases due to their effects on immune function. However, their immunopharmacological aspects in the present state of knowledge are not precisely comprehensible. Only a clear pathophysiological understanding could lead to an efficient strategy for breast cancer prevention and decrease in the mortality due to this disease.
Topics: Animals; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Autoimmune Diseases; Breast Neoplasms; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogens; Female; Gonadotropin-Releasing Hormone; Humans; Immunologic Factors; Male; Selective Estrogen Receptor Modulators
PubMed: 22750814
DOI: 10.2478/v10007-012-0012-3 -
Women's Health (London, England) Nov 2013Premenstrual dysphoric disorder (PMDD) is comprised of a cluster of affective, behavioral and somatic symptoms recurring monthly during the luteal phase of the menstrual... (Review)
Review
Premenstrual dysphoric disorder (PMDD) is comprised of a cluster of affective, behavioral and somatic symptoms recurring monthly during the luteal phase of the menstrual cycle. The disorder affects 3-8% of menstruating women and represents the more severe and disabling end of the spectrum of premenstrual disorders, which includes premenstrual syndrome and premenstrual aggravation of underlying affective disorder. Rigorous and specific diagnostic criteria for PMDD were specified in the Diagnostic and Statistical Manual of Mental Disorders IV (1994) and reaffirmed in the Diagnostic and Statistical Manual of Mental Disorders V (2013) and, consequently, there has been a marked increase in well-designed, placebo-controlled studies evaluating treatment modalities. Although the exact pathogenesis of PMDD is still elusive, treatment of PMDD and severe premenstrual syndrome has centered on neuromodulation via serotonin reuptake inhibitor antidepressants, and ovulation suppression utilizing various contraceptive and hormonal preparations. Unlike the approach to the treatment of depression, serotonergic antidepressants need not be given daily, but can be effective when used cyclically, only in the luteal phase or even limited to the duration of the monthly symptoms. Less, well-substantiated alternative treatments, such as calcium supplementation, agnus castus (chasteberry), Hypericum perforatum (St John's wort) and cognitive/behavioral/relaxation therapies, may be useful adjuncts in the treatment of PMDD. This review provides an overview of current information on the treatment of PMDD.
Topics: Contraceptives, Oral, Hormonal; Danazol; Estrogen Antagonists; Estrogens; Female; Gonadotropin-Releasing Hormone; Humans; Mood Disorders; Premenstrual Syndrome; Selective Serotonin Reuptake Inhibitors
PubMed: 24161307
DOI: 10.2217/whe.13.62 -
Women's Health (London, England) May 2008For several decades, clinicians have been prescribing hormone therapy to postmenopausal women for approved indications, including the alleviation of vasomotor symptoms,... (Review)
Review
For several decades, clinicians have been prescribing hormone therapy to postmenopausal women for approved indications, including the alleviation of vasomotor symptoms, relief of vaginal dryness and prevention of osteoporosis. Numerous publications have demonstrated that estrogen also induces favorable effects on lipids, the endothelium, cardiovascular outcomes, quality of life, cognition, skin and urinary incontinence. As a result of these findings, clinicians began adding each of these outcomes to their list of possible benefits of hormone therapy in postmenopausal women. Results from the Women's Health Initiative significantly changed this treatment paradigm and opened the door for new, innovative therapies for the prevention of clinical conditions encountered by women of menopausal age. One such treatment option is the estrogen agonist/antagonist. In this regard, investigators and clinicians alike seek a therapy that will act like estrogen in all the 'right' tissues and act as an estrogen antagonist in tissues in which estrogen action results in adverse events. This review describes the molecular actions of estrogen agonists/antagonists, discusses the current clinical data regarding the effect of these compounds on menopause-associated outcomes, and describes what is currently known about the effects of combining estrogen with an estrogen agonist/antagonist.
Topics: Clinical Trials as Topic; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Female; Humans; Menopause; Quality of Life; Treatment Outcome; Women's Health
PubMed: 19072475
DOI: 10.2217/17455057.4.3.257 -
Polskie Archiwum Medycyny Wewnetrznej 2014In Western countries, breast cancer is the most common cancer in women but available interventions can reduce risk. The aim of the paper was to review the available... (Review)
Review
In Western countries, breast cancer is the most common cancer in women but available interventions can reduce risk. The aim of the paper was to review the available evidence regarding breast cancer chemoprevention trials. A systematic literature search was conducted to identify all full‑scale, randomized prospective chemoprevention trials as well as similarly conducted randomized trials with breast cancer as the primary monitoring endpoint. In full‑scale, randomized chemoprevention trials, the selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, reduce breast cancer incidence. In a direct comparison, tamoxifen resulted in greater breast cancer reduction than raloxifene but with greater endometrial cancer risk. The aromatase inhibitors, exemestane and anastrozole, also reduce breast cancer incidence in breast cancer prevention trials. In the Women's Health Initiative hormone therapy trials, in postmenopausal women with no prior hysterectomy, estrogen plus progestin increased breast cancer incidence and deaths from breast cancer, while estrogen alone, in women with prior hysterectomy, reduced breast cancer incidence and reduced deaths from breast cancer. For premenopausal women at increased breast cancer risk, tamoxifen is a proven option with favorable side effect profile. For postmenopausal women, while no direct comparison of SERMs and aromatase inhibitors for chemoprevention are available, cross‑study comparisons suggest greater efficacy and more favorable side effect profile for aromatase inhibitor use, especially for older women. The opposite effects of estrogen plus progestin compared with estrogen alone on breast cancer incidence and outcome should factor into risk‑benefit consideration when these agents are considered for climacteric symptom management.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemoprevention; Estrogen Antagonists; Estrogens; Female; Humans; Incidence; Nitriles; Postmenopause; Premenopause; Prospective Studies; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Tamoxifen; Treatment Outcome; Triazoles
PubMed: 24618912
DOI: 10.20452/pamw.2190 -
Journal of Microbiology (Seoul, Korea) Feb 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene's mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.
Topics: Antiviral Agents; Drug Repositioning; Estrogen Antagonists; Estrogens; Humans; Molecular Docking Simulation; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; SARS-CoV-2; Selective Estrogen Receptor Modulators; COVID-19 Drug Treatment
PubMed: 33527314
DOI: 10.1007/s12275-021-0617-7 -
Endokrynologia Polska 2020Not required for Clinical Vignette.
Not required for Clinical Vignette.
Topics: Breast; Child; Estrogen Antagonists; Female; Humans; Hypertrophy
PubMed: 31909454
DOI: 10.5603/EP.a2019.0063 -
Breast Cancer Research and Treatment Apr 2020The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment...
PURPOSE
The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER.
METHODS
The pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo).
RESULTS
G1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib.
CONCLUSIONS
These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Resistance, Neoplasm; Estrogen Antagonists; Female; HIV Antibodies; Humans; Mice; Neoplasms, Hormone-Dependent; Protein Kinase Inhibitors; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 32130619
DOI: 10.1007/s10549-020-05575-9