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Purpose Enobosarm (EN), a selective androgen receptor modulator and raloxifene (RAL), a selective estrogen receptor modulator, have been shown to improve bone tissue in osteoporotic males. The present study evaluated the effects of a combination therapy of EN and RAL on bone properties in orchiectomized rats compared to the respective single treatments. Methods Eight-month-old male Sprague–Dawley rats were either left intact (Non-Orx) or orchiectomized (Orx). The Orx rats were divided into four groups (n = 15 each): 1) Orx, 2) EN treatment (Orx + EN), 3) RAL treatment (Orx + RAL), 4) combined treatment (Orx + EN + RAL). EN and RAL (0.4 mg and 7 mg/kg body weight/day) were applied immediately after Orx with a soy-free pelleted diet for up to 18 weeks. The lumbar spine and femora were examined by micro-CT, biomechanical, histomorphological, ashing, and gene expression analyses. Results EN exhibited an anabolic effect on bone, improving some of its parameters in Orx rats, but did not affect biomechanical properties. RAL exhibited antiresorptive activity, maintaining the biomechanical and trabecular parameters of Orx rats at the levels of Non-Orx rats. EN + RAL exerted a stronger effect than the single treatments, improving most of the bone parameters. Liver weight increased after all treatments; the kidney, prostate, and levator ani muscle weights increased after EN and EN + RAL treatments. BW was reduced due to a decreased food intake in the Orx + RAL group and due a reduced visceral fat weight in the Orx + EN + RAL group. Conclusion The EN + RAL treatment appeared to be promising in preventing male osteoporosis, but given the observed side effects on liver, kidney, and prostate weights, it requires further investigation.

Significant underutilization of breast cancer chemoprevention remains, despite guidelines stating that physicians should recommend chemoprevention with antiestrogen therapy to high-risk women. We randomized women, ages 35 to 75 years, who met high-risk criteria for breast cancer, without a personal history of breast cancer or prior chemoprevention use, to standard educational materials alone or combined with a web-based decision aid. All healthcare providers, including primary care providers and breast specialists, were given access to a web-based decision support tool. The primary endpoint was chemoprevention uptake at 6 months. Secondary outcomes included decision antecedents (perceived breast cancer risk/worry, chemoprevention knowledge, self-efficacy) and decision quality (decision conflict, chemoprevention informed choice) based upon patient surveys administered at baseline, 1 and 6 months after randomization. Among 282 evaluable high-risk women enrolled from November 2016 to March 2020, mean age was 57 years (SD, 9.9) and mean 5-year invasive breast cancer risk was 2.98% (SD, 1.42). There was no significant difference in chemoprevention uptake at 6 months between the intervention and control groups (2.1% vs. 3.5%). Comparing the intervention and control arms at 1 month, there were significant differences among high-risk women in accurate breast cancer risk perceptions (56% vs. 39%, P = 0.017), adequate chemoprevention knowledge (49% vs. 27%, P < 0.001), mean decision conflict (34.0 vs. 47.0, P < 0.001), and informed choice (41% vs. 23%, P = 0.003). These differences were no longer significant at 6 months. Although our decision support tools did not result in a significant increase in chemoprevention uptake, we did observe improvements in decision antecedents and decision quality measures. Prevention Relevance: In this randomized controlled trial of decision support for 300 high-risk women and 50 healthcare providers, we did not observe a significant increase in chemoprevention uptake, which remained low at under 5%. However, these decision support tools may increase knowledge and informed choice about breast cancer chemoprevention.

BACKGROUND Globally, breast cancer has been identified as the most common cancer among women. The clinical efficacy of adjuvant oral antiestrogen therapy-including tamoxifen and aromatase inhibitors-has been proven to be clinically efficacious for breast cancer survivors. However, medication adherence for these therapies remains suboptimal among breast cancer survivors. OBJECTIVE The aim of this study was to evaluate the effect of a reminder intervention-a smart pill bottle paired with the Pillsy mobile application-on medication adherence, medication self-efficacy, and depression, among breast cancer survivors who were undergoing oral antiestrogen therapy. METHODS This study is a randomized controlled trial. Sixty-one women were allocated to an experimental group (n = 31) and the control group (n = 30). The experimental group received the reminder intervention of a smart pill bottle for 4 weeks. Study outcomes were identified as medication adherence, medication self-efficacy, and depression. RESULTS Fifty-seven women completed the follow-up measurement. Significant differences in favor of the experimental group were noted for medication adherence (P = .004) and medication self-efficacy (P = .004). There was no statistically significant difference between the 2 groups with regard to depression (P = .057). CONCLUSIONS Reminder intervention using smart pill bottles was effective in improving medication adherence and medication self-efficacy among breast cancer survivors undergoing oral antiestrogen therapy. IMPLICATIONS FOR PRACTICE A smart pill bottle method of intervention can be a useful reminder strategy to improve medication adherence among breast cancer survivors.

Estrogen receptor-positive (ER+) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs) and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER+ breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; alterations in tumor microenvironment, nutrient stress and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6 and the Phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation selective estrogen receptor modulators (SERDs), AKT inhibitors, epidermal growth factor receptor 1 &2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and on-going clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER+ breast cancer patients.

Approximately one-third of estrogen receptor (ER) positive breast tumors fail to respond to or become resistant to hormonal therapy. Although the mechanisms responsible for hormone resistance are not completely understood, resistance is associated with alterations in ERα; overexpression of proteins that interact with the receptor; and hormone-independent activation of the receptor by growth factor signal transduction pathways. Our previous studies show that in estrogen dependent breast cancer cells, activation of the epidermal growth factor signaling pathway increases intracellular calcium which binds to and activates ERα through sites in the ligand-binding domain of the receptor and that treatment with extracellular calcium increases the concentration of intracellular calcium which activates ERα and induces hormone-independent cell growth. The present study asked whether overexpression of calcium channels contributes to the hormone-independent and -resistant phenotype of breast cancer cells and whether clinically used calcium channel blockers reverse hormone independence and resistance. The results show that hormone-independent and -resistant cells overexpress calcium channels, have high concentrations of intracellular calcium, overexpress estrogen responsive genes and, as expected, grow in the absence of estradiol and that treatment with calcium channel blockers decreased the concentration of intracellular calcium, the expression of estrogen responsive genes and cell growth. More importantly, in hormone-resistant cells, treatment that combined a calcium channel blocker with an antiestrogen reversed resistance to the antiestrogen.

Objectives: Antiresorptive treatment has been shown to impair mucosal cell proliferation, migration, and viability. However, in the clinic, antiresorptives are often used in combination with other drugs. We studied the effect of antiresorptives combined with a corticosteroid or antiestrogen on oral mucosal keratinocytes and fibroblasts. Material and methods: Human gingival keratinocyte and fibroblast cell lines were exposed to bisphosphonates (BPs) and denosumab in different concentrations and durations together with an antiestrogen or corticosteroid. Changes in cell viability, proliferation and migration after exposures were measured. Data were evaluated with hierarchical linear mixed model for repeated measurements. Results: Bisphosphonate exposure suppressed keratinocyte and fibroblast cell viability, proliferation, and migration in a time-dependent manner. Combining a corticosteroid or antiestrogen with BPs further increased this negative effect. Denosumab alone had a mild positive effect on keratinocyte and fibroblast growth. When denosumab was combined with a corticosteroid or antiestrogen, cell growth was suppressed. Conclusions: Our results show that coexisting medications may increase the negative impact of BPs or denosumab on oral mucosal cells.

Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER + breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome.

The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens., The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes responsible endocrine resistance in this region are unclear. In this study, the authors demonstrate that PRR11 located at 17q23, is critical for conferring endocrine resistance through activation of PI3K signalling and therefore propose PI3K inhibition as a treatment for PRR11-amplified breast cancers.

27-hydroxycholesterol (27-HC) is the first known endogenous selective estrogen receptor modulator (SERM), and its elevation from normal levels is closely associated with breast cancer. A plethora of evidence suggests that aberrant epigenetic signatures in breast cancer cells can result in differential responses to various chemotherapeutics and often leads to the development of resistant cancer cells. Such aberrant epigenetic changes are mostly dictated by the microenvironment. The local concentration of oxygen and metabolites in the microenvironment of breast cancer are known to influence the development of breast cancer. Hence, we hypothesized that 27-HC, an oxysterol, which has been shown to induce breast cancer progressionviaestrogen receptor alpha (ERα) and liver X receptor (LXR) and by modulating immune cells, may also induce epigenetic changes. For deciphering the same, we treated the estrogen receptor-positive cells with 27-HC and identified DNA hypermethylation on a subset of genes by performing DNA bisulfite sequencing. The genes that showed significant DNA hypermethylation werephosphatidylserine synthase 2 (PTDSS2), MIR613, indoleamine 2,3-dioxygenase 1 (IDO1), thyroid hormone receptor alpha (THRA), dystrotelin (DTYN),andmesoderm induction early response 1, family member 3 (MIER). Furthermore, we found that 27-HC weakens the DNMT3B association with the ERα in MCF-7 cells. This study reports that 27-HC induces aberrant DNA methylation changes on the promoters of a subset of genes through modulation of ERα and DNMT3B complexes to induce the local DNA methylation changes, which may dictate drug responses and breast cancer development.

PurposeCancer patients are concerned about treatment-related cognitive problems. We examined effects of antiestrogen hormonal therapy on brain imaging metrics in older women with breast cancer.MethodsWomen aged 60+ treated with hormonal therapy only and matched non-cancer controls (n=29/group) completed MRI and objective and self-reported cognitive assessment at pre-treatment/enrollment and 12 months later. Gray matter was examined using voxel-based morphometry (VBM), FreeSurfer, and brain age calculations. Functional MRI (fMRI) assessed working memory-related activation. Analyses examined cross-sectional and longitudinal differences and tested associations between brain metrics, cognition, and days on hormonal therapy.ResultsThe cancer group showed regional reductions over 12 months in frontal, temporal, and parietal gray matter on VBM, reduced FreeSurfer cortical thickness in prefrontal, parietal, and insular regions, and increased working memory-related fMRI activation in frontal, cingulate, and visual association cortex. Controls showed only reductions in fusiform gyrus on VBM and FreeSurfer temporal and parietal cortex thickness. Women with breast cancer showed higher estimated brain age and lower regional gray matter volume than controls at both timepoints. The cancer group showed a trend toward decreased performance in attention, processing speed, and executive function over time. There were no significant associations between brain imaging metrics and cognition or days on hormonal therapy.ConclusionOlder women with breast cancer showed brain changes in the first year of hormonal therapy. Increased brain activation during working memory processing may be a sign of functional compensation for treatment-related structural changes. This hypothesis should be tested in larger samples over longer time periods.

Purpose of review Uterine fibroids are the most common benign neoplasms of the female reproductive tract and one of the major public health concerns. Although most women with uterine fibroids are asymptomatic, over 30% of them will present with varying symptoms. This review focuses on the role of non-hormonal mediators and pathways in uterine fibroid biology. Furthermore, it provides data regarding the most recent findings in the field of compounds, which use those non-hormonal pathways in the medical therapy of uterine fibroids. Recent findings Complex signaling pathway alterations are crucial for uterine fibroid development. The topic of the pathophysiology of uterine fibroids focuses mostly on steroids and other hormones. However, other very important pathways exist, and some of them are independent of hormones. Some of the most important pathways, which are non-hormonal, but in some cases still hormone-depended, include growth factors, cytokines and inflammation, Smad proteins, wingless type/β-catenin and others. Summary Much more is known about hormonal than about non-hormonal signaling in uterine fibroids. Growth factors, early life exposure and inflammation are key factors in uterine fibroid biology. Numerous agents depend on those pathways and may find their place in the current and future therapy of uterine fibroids.

Recently, we have shown that changes in Fourier transform infrared (FTIR) spectra of living MDA-MB-231 cells (a triple negative cell line) upon exposure to anticancer drugs reflect the changes in the cellular compositions which are correlated to the modes of action of drugs. In the present study, MCF7 cells (an estrogen receptor expressing breast cancer cell line) were exposed to three anticancer drugs belonging to two well-characterized anticancer classes: selective estrogen receptor modulators (SERMs) and DNA-intercalating agent. First, we evaluated if the changes in the spectrum of cells are according to the modes of action of drugs and the characteristics of the MCF7 cell line in the same way as the MDA-MB-231 cell. Living MCF7 cells were treated in the three drugs at half maximal inhibitory concentration (IC50), and the difference spectra were analyzed using principal component analysis (PCA). The results demonstrated clear separation between tamoxifen/toremifene (SERM)-treated cells from the doxorubicin (DNA-intercalator)-treated and untreated cells (control). Tamoxifen and toremifene induced similar spectral changes in the cellular compositions of MCF7 cells and lead to the clustering of these two drugs in the same quadrant of the principal component 1 (PC1) versus PC2 score plots. The separation is mostly attributed to their similar modes of actions. However, doxorubicin-treated MCF7 cells highlighted spectral changes that mainly occur in bands at 1085 and 1200-1240 cm-1, which could be associated with the DNA-intercalation effects of the drug. Second, the pairwise PCA at various individual time points was employed to investigate whether the spectral changes of MCF7 and MDA-MB-231 cells in response to the IC50 of tamoxifen/toremifene and doxorubicin are dependent on the characteristics of the cell lines. The estrogen-expressing MCF7 cells demonstrated significant differences in response to the SERMs in comparison to the triple negative MDA-MB-231 cells, suggesting that different modes of action have taken place in the two tested cell lines. In contrast, the doxorubicin-treated MDA-MB-231 and MCF7 cells show similar changes in 1150-950 cm-1, which indicates that the DNA intercalation effect of doxorubicin is found in both cell lines. The results have demonstrated that live-cell FTIR analysis is sensitive to the different modes of action from the same drugs on cells with different characteristics.

As a standard treatment, endocrine therapy has dramatically enhanced the prognosis of patients with estrogen receptor (ER)-positive breast cancer, which accounts for nearly 70% of all breast cancers. Antiestrogen drugs such as tamoxifen and aromatase inhibitors are the standard treatment options for ERα-positive breast cancer. However, acquired antiestrogen resistance is still the leading cause of disease recurrence and progression. Evidence has shown that long noncoding RNAs (lncRNAs) play an essential role in the development of antiestrogen resistance in ER-positive breast cancer and can serve as biomarkers or potential therapeutic targets. This review highlights the role of lncRNAs in the development of antiestrogen resistance in breast cancer.

Background Targeting vulnerabilities of cancer cells by inhibiting key regulators of cell proliferation or survival represents a promising way to overcome resistance to current therapies. In breast cancer (BC), resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ERα) signaling to the genome. Targeting components of the ERα pathway in these tumors represents, therefore, a rational way toward effective new treatments. Interaction proteomics identified several proteins associated with ERα in BC cells, including epigenetic complexes controlling gene transcription comprising the scaffold protein menin and the histone methyltransferase Dot1L. Methods We combined chromatin immunoprecipitation, transcriptome sequencing, siRNA-mediated gene knockdown (kd), pharmacological inhibition coupled to cellular and functional assays and interaction proteomics in antiestrogen (AE)-sensitive and AE-resistant human BC cell models to: map menin and Dot1L chromatin localization, search for their common and specific target genes, measure the effects of single or combinatorial knockdown or pharmacological inhibition of these proteins on cell proliferation and survival, and characterize their nuclear interactomes. Results Dot1L and menin associate in MCF-7 cells chromatin, where they co-localize in a significant fraction of sites, resulting in co-regulation of genes involved, among others, in estrogen, p53, HIF1α and death receptor signaling, regulation of cell cycle and epithelial-to-mesenchymal transition. Specific inhibitors of the two factors synergize with each other for inhibition of cell proliferation of AE (tamoxifen or fulvestrant)-sensitive and AE-resistant BC cells. Menin and Dot1L interactomes share a sizeable fraction of their nuclear partners, the majority being known BC fitness genes. Interestingly, these include B-WICH and WINAC complexes that share BAZ1B, a bromodomain protein comprising a tyrosine–protein kinase domain playing a central role in chromatin remodeling and transcriptional regulation. BAZ1B kd caused significant inhibition of ERα expression, proliferation and transcriptome changes resulting in inhibition of estrogen, myc, mTOR, PI3K and AKT signaling and metabolic pathways in AE-sensitive and AE-resistant BC cells. Conclusions Identification of a functional interplay between ERα, Dot1L, menin and BAZ1B and the significant effects of their co-inhibition on cell proliferation and survival in cell models of endocrine therapy-resistant BC reveal a new therapeutic vulnerability of these aggressive diseases.

Owing to the ongoing coronavirus disease 2019 (COVID-19) pandemic, we need to pay a particular focus on the impact of coronavirus infection on breast cancer patients. Approximately 70% of breast cancer patients express estrogen receptor (ER), and intervention therapy for ER has been the primary treatment strategy to prevent the development and metastasis of breast cancer. Recent studies have suggested that selective estrogen receptor modulators (SERMs) are a potential therapeutic strategy for COVID-19. With its anti-ER and anti-viral combined functions, SERMs may be an effective treatment for COVID-19 in patients with breast cancer. In this review, we explore the latent effect of SERMs, especially tamoxifen, and the mechanism between ER and virus susceptibility.

The absence of leptin results in contrasting growth pattern of appendicular and axial bone growth in ob/ob mice. Endochondral bone formation is an important procedure of growth plate determining the bone growth, where this procedure is also regulated by estrogen and its receptor (ER) signaling pathway. The present study is undertaken to explore the roles of ERs in regulating the different growth patterns in ob/ob mice. In this study, C57BL/6 female mice were used as wild-type (WT) mice; ob/ob mice and WT mice were age-matched fed, and bone length is analyzed by X-ray plain film at the 12 weeks old. We confirm that ob/ob mice have shorter femoral length and longer spine length than WT mice (p < 0.05). The contrasting expression patterns of chondrocyte proliferation proteins and hypertrophic marker proteins are also observed from the femur and spinal growth plate of ob/ob mice compared with WT mice (p < 0.01). Spearman’s analysis showed that body length (axial and appendicular length) is positively related to the expression level of ERα in growth plate. Three-week-old female ob/ob mice are randomized divided into three groups: 1) ob/ob + ctrl, 2) ob/ob + ERα antagonist (MPP), and 3) ob/ob + ERβ antagonist (PHTPP). Age-matched C57BL/6 mice were also divided into three groups, same as the groups of ob/ob mice. MPP and PHTPP were administered by intraperitoneal injection for 6 weeks. However, the results of X-ray and H&E staining demonstrate that leptin deficiency seems to disturb the regulating effects of ER antagonists on longitudinal bone growth. These findings suggested that region-specific expression of ERα might be associated with contrasting phenotypes of axial and appendicular bone growth in ob/ob mice. However, ER signaling on longitudinal bone growth was blunted by leptin deficiency in ob/ob mice, and the underlying association between ERs and leptin needs to be explored in future work.

Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.

Based on previous evidence that the non-steroidal estrogen receptor modulator STX mitigates the effects of neurotoxic Amyloid-β (Aβ) in vitro, we have evaluated its neuroprotective benefits in a mouse model of Alzheimer's disease. Cohorts of 5XFAD mice, which begin to accumulate cerebral Aβ at two months of age, were treated with orally-administered STX starting at 6 months of age for two months. After behavioral testing to evaluate cognitive function, biochemical and immunohistochemical assays were used to analyze key markers of mitochondrial function and synaptic integrity. Oral STX treatment attenuated Aβ-associated mitochondrial toxicity and synaptic toxicity in the brain, as previously documented in cultured neurons. STX also moderately improved spatial memory in 5XFAD mice. In addition, STX reduced markers for reactive astrocytosis and microgliosis surrounding amyloid plaques, and also unexpectedly reduced overall levels of cerebral Aβ in the brain. The neuroprotective effects of STX were more robust in females than in males. These results suggest that STX may have therapeutic potential in Alzheimer's Disease.

Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs.

COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient’s organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.