Selective Estrogen Receptor Modulators Research Articles

USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERα.

Breast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics. We used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance. In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer. Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.

Estrogen Receptors: A New Frontier in Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a long-term neurodegenerative condition that leads to the deterioration of neurons and synapses in the cerebral cortex, resulting in severe dementia. AD is significantly more prevalent in postmenopausal women, suggesting a neuroprotective role for estrogen. Estrogen is now known to regulate a wide array of physiological functions in the body by interacting with three known estrogen receptors (ERs) and with the β-amyloid precursor protein, a key factor in AD pathogenesis. Recent experimental evidence indicates that new selective ER modulators and phytoestrogens may be promising treatments for AD for their neuroprotective and anti-apoptotic properties. These alternatives may offer fewer side effects compared to traditional hormone therapies, which are associated with risks such as cardiovascular diseases, cancer, and metabolic dysfunctions. This review sheds light on estrogen-based treatments that may help to partially prevent or control the neurodegenerative processes characteristic of AD, paving the way for further investigation in the development of estrogen-based treatments.

Antiviral Activity of Selective Estrogen Receptor Modulators against Severe Fever with Thrombocytopenia Syndrome Virus In Vitro and In Vivo.

Severe fever with thrombocytopenia syndrome virus (SFTSV), also known as the Dabie Banda virus, is an emerging tick-borne Bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS). Currently, symptomatic treatment and antiviral therapy with ribavirin and favipiravir are used in clinical management. However, their therapeutical efficacy is hardly satisfactory in patients with high viral load. In this study, we explored the antiviral effects of selective estrogen receptor modulators (SERMs) on SFTSV infection and the antiviral mechanisms of a representative SERM, bazedoxifene acetate (BZA). Our data show that SERMs potently inhibited SFTSV-induced cytopathic effect (CPE), the proliferation of infectious viral particles, and viral RNA replication and that BZA effectively protected mice from lethal viral challenge. The mode of action analysis reveals that BZA exerts antiviral effects during the post-entry stage of SFTSV infection. The transcriptome analysis reveals that GRASLND and CYP1A1 were upregulated, while TMEM45B and TXNIP were downregulated. Our findings suggest that SERMs have the potential to be used in the treatment of SFTSV infection.

Beyond breast cancer: role of selective estrogen receptor modulators in reducing systemic malignancies: evidence from population-based data

Background Raloxifene and bazedoxifene are selective estrogen receptor modulators (SERMs) used to prevent and treat osteoporosis in postmenopausal women. Raloxifene is also known for its preventive effect against invasive breast cancer; however, its effect on other cancer types is unclear. This study investigated the incidence of various cancers in osteoporosis patients receiving SERM therapy to determine its association with the risk of developing specific cancer types. Methods This retrospective cohort study examined the association between SERM use and the incidence of cervical, endometrial, ovarian, and colorectal cancers in postmenopausal women using data from the Korean National Health Insurance Service. Propensity score matching ensured group comparability by analyzing 95,513 participants. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the cancer risk associated with SERM therapy, differentiating between the effects of raloxifene and bazedoxifene. Results SERM therapy was associated with a reduced risk of cervical (adjusted HR = 0.47, 95% CI = 0.31–0.71), ovarian (adjusted HR = 0.61, 95% CI = 0.42–0.88), and colorectal cancer (adjusted HR = 0.49, 95% CI = 0.42–0.57). No significant risk reduction was observed for endometrial cancer (adjusted HR = 1.05, 95% CI = 0.70–1.59). A comparison between raloxifene and bazedoxifene revealed no significant differences in their cancer prevention effects. Conclusion SERM therapy administration is associated with a decreased incidence of cervical, ovarian, and colorectal cancers. Notably, the effects of raloxifene and bazedoxifene were consistent. Further investigations are crucial to elucidate the mechanisms underlying these observations and their clinical implications.

Graphene oxide nanoribbons conjugated with 1, 2-distearoyl-sn-glycero-3 phosphoethanolamine-poly (ethylene glycol)-transferrin enhanced targeted delivery and cytotoxicity of raloxifene against breast cancer

The clinical utility of raloxifene (RLX), a selective estrogen receptor modulator (SERM), has been compromised by severe side effects and unfavorable drug properties. To address these, a transferrin (Tf) conjugated graphene oxide nanoribbon (GONR) platform was tried for RLX. The stability of GONRs in biological media was improved by surface modification with 1, 2-Distearoyl-sn-glycero-3 phosphoethanolamine-Poly (ethylene glycol) (DSPE-PEG). The Tf molecule was covalently attached to DSPE-PEG (DPT) using EDC-NHS chemistry. The surface of GONR was then modified with DSPE-PEG (DP) or DPT and loaded with RLX (GDP-RLX and GDPT-RLX). The final formulations were characterized for drug loading and stability. The anticancer activities of pure RLX, GDP-RLX, and GDPT-RLX were evaluated and compared in all the in vitro and in vivo studies. In vitro cell line studies showed that GDPT-RLX have significantly high cytotoxicity, cellular uptake, apoptosis induction, G2/M phase arrest, anti-migration properties, and apoptotic protein expression, followed by GDP-RLX and RLX. Pharmacokinetics and tumor biodistribution were also found to be excellent with GDPT-RLX. The in vivo tumor therapy and tumor evaluation outcomes were also consistent with the in vitro data. The Tf conjugated GDPT-RLX represents a promising approach for targeted and sustained delivery of RLX with enhanced therapeutic efficacy.

Ocular surface adverse reactions of antitumor-targeted drugs

With the extensive application of targeted drugs, the survival rate of cancer patients has been significantly improved. However, adverse reactions to the drugs have also become apparent, especially those affecting the ocular surface, which can severely impact patients' vision and quality of life. The article systematically analyzes a variety of targeted drugs, including epidermal growth factor receptor inhibitors, human epidermal growth factor receptor 2 inhibitors, fibroblast growth factor receptor inhibitors, selective estrogen receptor modulators, vascular endothelial growth factor receptor inhibitors, aromatase inhibitors, proteasome inhibitors, antibody-drug conjugates, Bruton's tyrosine kinase inhibitors, FMS-like tyrosine kinase 3 inhibitors, and cyclin-dependent kinase inhibitors, and discusses their adverse reactions on the ocular surface. The review emphasizes the role of clinicians in monitoring and managing patients' ocular surface health and the importance of early diagnosis and intervention to ensure that patients receive optimal visual protection while undergoing antitumor treatment.

Association of Adiposity Phenotypes with 27-Hydroxycholesterol and Sex Hormones: The Multiethnic Cohort Study.

The distribution of body fat has been linked to circulating levels of lipids and sex-steroid hormones. The cholesterol metabolite and endogenous selective estrogen receptor modulator, 27-hydroxychlolesterol (27HC), may be influenced by adiposity phenotypes, particularly among females. No study has examined the relationships of 27HC and steroid hormones with adiposity phenotypes. To investigate the associations of 27HC and steroid hormones with detailed adiposity phenotypes among a multiethnic population of postmenopausal females. A cross-sectional study was conducted among 912 postmenopausal females from the Multiethnic Cohort- Adiposity Phenotype study. Multivariable linear regression examined the associations of circulating levels of 27HC, steroid hormones, and sex hormone-binding globulin (SHBG) with detailed adiposity phenotypes, adjusting for demographics, lifestyle factors, diabetes status, and use of lipid lowering drugs. Subgroup analyses were conducted across race and ethnicity. Total fat mass (P-trend=0.003), subcutaneous adipose tissue (SAT) (P-trend=0.006), and superficial subcutaneous adipose tissue (sSAT) (P-trend=4.41x10-4) were inversely associated with circulating 27HC levels. In contrast, visceral adipose tissue (VAT) (P-trend=0.003) and liver fat (P-trend=0.005) were positively associated with 27HC levels. All adiposity phenotypes were associated with higher levels of free estradiol, testosterone and lower levels of SHBG. Generally, similar patterns of associations were observed across race and ethnicity. Adiposity phenotypes, such as SAT, VAT, and liver fat, were differentially associated with circulating 27HC, while consistent directions of associations were seen for circulating hormones among postmenopausal females. Future studies are warranted to further understand the biology and relationships of 27HC and adiposity-related diseases.

Selective Estrogen Receptor Modulators' (SERMs) Influence on TET3 Expression in Breast Cancer Cell Lines with Distinct Biological Subtypes.

Tamoxifen, a selective estrogen receptor modulator (SERM), exhibits dual agonist or antagonist effects contingent upon its binding to either G-protein-coupled estrogen receptor (GPER) or estrogen nuclear receptor (ESR). Estrogen signaling plays a pivotal role in initiating epigenetic alterations and regulating estrogen-responsive genes in breast cancer. Employing three distinct breast cancer cell lines-MCF-7 (ESR+; GPER+), MDA-MB-231 (ESR-; GPER-), and SkBr3 (ESR-; GPER+)-this study subjected them to treatment with two tamoxifen derivatives: 4-hydroxytamoxifen (4-HT) and endoxifen (Endox). Through 2D high-performance liquid chromatography with tandem mass spectrometry detection (HPLC-MS/MS), varying levels of 5-methylcytosine (5-mC) were found, with MCF-7 displaying the highest levels. Furthermore, TET3 mRNA expression levels varied among the cell lines, with MCF-7 exhibiting the lowest expression. Notably, treatment with 4-HT induced significant changes in TET3 expression across all cell lines, with the most pronounced increase seen in MCF-7 and the least in MDA-MB-231. These findings underscore the influence of tamoxifen derivatives on DNA methylation patterns, particularly through modulating TET3 expression, which appears to be contingent on the presence of estrogen receptors. This study highlights the potential of targeting epigenetic modifications for personalized anti-cancer therapy, offering a novel avenue to improve treatment outcomes.

Dynamic methylation and expression of alternative promoters for oestrogen receptor alpha in cell line models of fulvestrant resistance.

Oestrogen receptor alpha (ER; gene symbol ESR1) is the most important prognostic and treatment-predictive biomarker in breast cancer. Drugs targeting oestrogen and ER for endocrine therapy of breast cancer include aromatase inhibitors, the selective ER modulator tamoxifen and the selective ER degrader fulvestrant. Tumours can develop resistance to endocrine therapy through several mechanisms, which is often linked to altered expression of ER. To investigate the role of promoter methylation in the regulation of ESR1 expression, we used bisulfite sequencing to measure methylation at CpG sites in alternative ER promoter regions for six cell line models of fulvestrant resistance. Both CpG methylation and expression of alternative first exons changed dynamically, with striking differences between cell lines that had stable or unstable resistance upon fulvestrant withdrawal. Methylation at some CpG sites was strongly negatively correlated with expression of specific first exons. In a breast tumour cohort, higher relative expression of upstream alternative first exons was associated with worse prognosis in post-menopausal women with ER-positive tumours who received endocrine therapy.

Improving Tamoxifen Performance in Inducing Apoptosis and Hepatoprotection by Loading on a Dual Nanomagnetic Targeting System.

Although tamoxifen (TMX) belongs to selective estrogen receptor modulators (SERMs) and selectively binds to estrogen receptors, it affects other estrogen-producing tissues due to passive diffusion and non-differentiation of normal and cancerous cells and leads to side effects. The problems expressed about tamoxifen (TMX) encouraged us to design a new drug delivery system based on magnetic nanoparticles (MNPs) to simultaneously target two receptors on cancer cells through folic acid (FA) and hyaluronic acid (HA) groups. The mediator of binding of two targeting agents to MNPs is a polymer linker, including dopamine, polyethylene glycol, and terminal amine (DPN). Zeta potential, dynamic light scattering (DLS), and Field emission scanning electron microscopy (FESEM) methods confirmed that MNPs-DPN-HA-FA has a suitable size of ~105 nm and a surface charge of -41 mV, and therefore, it can be a suitable option for carrying TMX and increasing its solubility. The cytotoxic test showed that the highest concentration of MNPs-DPN-HA-FA-TMX decreased cell viability to about 11% after 72 h of exposure compared to the control. While the protective effect of modified MNPs on normal cells was evident, unlike tamoxifen, the survival rate of liver cells, even after 180 min of treatment, was not significantly different from the control group. The protective effect of MNPs was also confirmed by examining the amount of malondialdehyde, and no significant difference was observed in the amount of lipid peroxidation caused by modified MNPs compared to the control. Flow cytometry proved that TMX can induce apoptosis by targeting MNPs. Real-time PCR showed that the modified MNPs activated the intrinsic and extrinsic mitochondrial pathways of apoptosis, so the Bak1/Bclx ratio for MNPs-DPN-HA-FA-TMX and free TMX was 70.82 and 0.38, respectively. Also, the expression of the caspase-3 gene increased 430 times compared to the control. On the other hand, only TNF gene expression, which is responsible for metastasis in some tumors, was decreased by both free TMX and MNPs-DPN-HA-FA-TMX. Finally, molecular docking proved that MNPs-DPN-HA-FA-TMX could provide a very stable interaction with both CD44 and folate receptors, induce apoptosis in cancer cells, and reduce hepatotoxicity. All the results showed that MNPs-DPN-HA-FA-TMX can show good affinity to cancer cells using targeting agents and induce apoptosis in metastatic breast ductal carcinoma T-47D cell lines. Also, the protective effects of MNPs on hepatocytes are quite evident, and they can reduce the side effects of TMX.

Mechanistic Insights and Therapeutic Strategies in Osteoporosis: A Comprehensive Review.

Osteoporosis, a metabolic bone disorder characterized by decreased bone mass per unit volume, poses a significant global health burden due to its association with heightened fracture risk and adverse impacts on patients' quality of life. This review synthesizes the current understanding of the pathophysiological mechanisms underlying osteoporosis, with a focus on key regulatory pathways governing osteoblast and osteoclast activities. These pathways include RANK/RANKL/OPG, Wingless-int (Wnt)/β-catenin, and Jagged1/Notch1 signaling, alongside the involvement of parathyroid hormone (PTH) signaling, cytokine networks, and kynurenine in bone remodeling. Pharmacotherapeutic interventions targeting these pathways play a pivotal role in osteoporosis management. Anti-resorptive agents, such as bisphosphonates, estrogen replacement therapy/hormone replacement therapy (ERT/HRT), selective estrogen receptor modulators (SERMs), calcitonin, anti-RANKL antibodies, and cathepsin K inhibitors, aim to mitigate bone resorption. Conversely, anabolic agents, including PTH and anti-sclerostin drugs, stimulate bone formation. In addition to pharmacotherapy, nutritional supplementation with calcium, vitamin D, and vitamin K2 holds promise for osteoporosis prevention. However, despite the availability of therapeutic options, a substantial proportion of osteoporotic patients remain untreated, highlighting the need for improved clinical management strategies. This comprehensive review aims to provide clinicians and researchers with a mechanistic understanding of osteoporosis pathogenesis and the therapeutic mechanisms of existing medications. By elucidating these insights, this review seeks to inform evidence-based decision-making and optimize therapeutic outcomes for patients with osteoporosis.

Current treatment for male infertility: an umbrella review of systematic reviews and meta-analyses.

This umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments for male infertility and assess the quality of evidence and possible biases. An umbrella review of systematic reviews and meta-analyses available in PubMed, Web of Science, and Scopus, covering studies published up to October 2023, was conducted. Sperm concentration, morphology, and motility were used as endpoints to evaluate the effectiveness of the treatments. Of 2998 studies, 18 published meta-analyses were extracted, yielding 90 summary effects on sperm concentration (n = 36), sperm morphology (n = 26), and sperm motility (n = 28) on 28 interventions. None of the meta-analyses were classified as having low methodological quality, whereas 12 (66.7%) and 6 (33.3%) had high and moderate quality, respectively. Of the 90 summary effects, none were rated high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23), and 21.1% (n = 19) were rated moderate, low, and very low, respectively. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (N-acetyl-cysteine, antioxidant therapy, aromatase inhibitors, selective estrogen receptor modulators, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (varicocele repair and redo varicocelectomy). In addition, vitamin supplementation had no significant positive effects on sperm concentration, motility, or morphology. Treatments for male infertility are increasingly diverse; however, the current evidence is poor because of the limited number of patients. Further well-designed studies on single treatment and high-quality meta-analysis of intertreatment comparisons are recommended.

PSYCHOTIC DISORDER INDUCED BY CLOMIPHENE CITRATE IN A MAN: A RARE CASE REPORT

The clomiphene citrate is one of the selective estrogen receptor modulators and its function is to indirectly induce ovulation, stimulating the secretion of pituitary gonadotropins (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)), subsequently increasing testosterone circulation levels. Its main adverse effects include increased ovarian volume, vasomotor symptoms, pelvic discomfort, and hepatic dysfunction. However, some reactions to this medication may be unknown or poorly reported in the scientific literature. Hormonal effects may be responsible for the unfavorable psychotic outcomes in conjunction with the antiestrogenic activity of clomiphene. The appearance of psychotic symptoms, especially in women with a pre-existing psychiatric history, has been previously studied [1,4]. The effects were attributed to an enhanced testosterone-androgen receptor interaction in the brain, subsequently leading to alteration of emotional conditions. Proposed neurobiological targets include catecholaminergic cells in the hypothalamus and other limbic regions of the brain.). Nevertheless, the occurrence of such symptoms has not been reported in the literature in males. This letter aims to report the case of a 36-year-old male patient who presented an adverse reaction that is not clear in the literature on Clomiphene Citrate, since the majority of reported cases are in the female population with some previous psychiatric comorbidity. The patient had a previous diagnosis of fibromyalgia. Approximately 20 days after the introduction of the medication, he presented his first psychotic episode with manifest characteristics, with increased energy, hypersexualization, low need for sleep, grandiose delusions, impulsive and inappropriate behavior lasting an average of 4 days. The patient's family reported that he had never exhibited similar behavior. The second psychotic episode occurred approximately 20 days after the first. In the latter, the patient presented with persecutory delusions, risky behavior, paranoid behavior, risk of self- and hetero-aggression, and was taken to his first psychiatric hospitalization. It was reported that he used clomiphene citrate up to 15 days before psychiatric hospitalization. The use of other psychoactive substances was also ruled out (a toxicological test with a negative result) and admission and neuroimaging exams (magnetic resonance imaging of the skull) were carried out, with all results within normal limits. The patient was admitted to our service being introduced to valproic acid 1000mg/day, risperidone 2mg/day, quetiapine 100mg/day and gabapentin 900mg/day (already being used to treat chronic pain) and clomiphene was suspended. He presented rapid remission of delusions in two days with criticism present in the first week of hospitalization. Due to the absence of psychiatric history, as well as other possible causes for the appearance of symptoms, the psychotic condition described was therefore attributed to the use of clomiphene. Thus, the possibility of this medication inducing the appearance of symptoms should be considered, especially in patients experiencing their first psychotic episode [2,3].

27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.

Nongenomic ERα-AMPK Signaling Regulates Sex-Dependent Bcrp Transport Activity at the Blood-Brain Barrier.

The blood-brain barrier (BBB) is an extensive capillary network that protects the brain from environmental and metabolic toxins while limiting drug delivery to the central nervous system (CNS). The ATP-binding cassette transporter breast cancer resistance protein (Bcrp) reduces drug delivery across the BBB by actively transporting its clinical substrates back into peripheral circulation before their entry into the CNS compartment. 17β-Estradiol (E2)-elicited changes in Bcrp transport activity and expression have been documented previously. We report a novel signaling mechanism by which E2 decreases Bcrp transport activity in mouse brain capillaries via rapid nongenomic signaling through estrogen receptor α. We extended this finding to investigate the effects of different endocrine-disrupting compounds (EDCs) and selective estrogen receptor modulators (SERMs) on Bcrp transport function. We also demonstrate sex-dependent expression of Bcrp and E2-sensitive Bcrp transport activity at the BBB ex vivo. This work establishes an explanted tissue-based model by which to interrogate EDCs and SERMs as modulators of nongenomic estrogenic signaling with implications for sex and hormonal regulation of therapeutic delivery into the CNS.

Comparing the effects of low-level laser therapy and gaseous ozone as a preventive measure on medication-related osteonecrosis of the jaws following tooth extraction: a rat model

ObjectivesUse of numerous medications such as tyrosine kinase inhibitors (sunitinib), monoclonal antibodies (bevacizumab), fusion proteins (aflibercept), mTOR inhibitors (everolimus), radiopharmaceuticals (radium 223), selective estrogen receptor modulators (raloxifene), and immunosuppressants (methotrexate and corticosteroids) has been reported to be a risk factor for development of medication-related osteonecrosis of the jaws till date. This study aimed to evaluate the preventive effect of low-level laser therapy (LLLT) and gaseous ozone on the onset of MRONJ following tooth extraction.Materials and methodsA total of 40 male Wistar rats were randomly allocated into 4 groups of 10 rats each. The groups laser (L), ozone (O), and control (C) received weekly intraperitoneal injections of zoledronic acid (0.06 mg/kg), while group sham (S) received saline solution for 4 weeks. After the 4th injection, all subjects underwent mandibular first molar extraction and adjunctive laser or ozone was applied according to the groups. All the rats were sacrificed at 4 postoperative weeks for comparative histomorphometric evaluation of bone healing in extraction sites.ResultsLaser and ozone groups demonstrated significantly higher bone formation compared to control group (p < 0.05), while no significant difference was found between laser and ozone groups (p = 1.00). Furthermore, the greatest bone formation was observed with the sham group (p < 0.05).ConclusionsFindings of the current study support that adjunctive LLLT and ozone therapy following tooth extraction may help prevent MRONJ and improve bone healing in subjects under zoledronic acid therapy.Clinical relevanceSince the introduction in 2003, great effort has been devoted to developing a certain management protocol for MRONJ. Several publications have appeared in recent years documenting promising results of adjunctive LLLT and ozone application in treatment of MRONJ. However, experimental data are limited on this regard and the present study, for the first time, aimed to evaluate and compare the effects of LLLT and ozone in prevention of MRONJ.

Affinity for Estrogen Receptor α (ERα) in a &lt;i&gt;trans&lt;/i&gt;-Stilbene Derivative Containing a Pyridoxine Fragment

Molecular targets for a promising antitumor agent based on trans-stilbene containing a pyridoxine fragment were identified. The lead compound, (E)-6-(3,4-dimethoxystyryl)-2,2,5,8-tetramethyl-4H-[1,3] dioxino[4,5-c]pyridine, was found to selectively induce apoptosis in MCF-7 breast adenocarcinoma cells overexpressing estrogen receptor, but not in MDA-MB-231 cells negative for estrogen receptor. The mechanism by which the novel trans-stilbene derivative acts as a selective estrogen receptor modulator was analyzed, and the affinity for human estrogen receptor α (ERα) was assessed by fluorescence polarization. Unlike its structural analogs—tamoxifen and raloxifene, the lead compound showed no affinity for ERα and did not form complexes with it. Therefore, it was concluded that the selective action of the pyridoxine-containing derivative of trans-stilbene on estrogen-positive breast cancer cells occurs through an alternative mechanism. The EC 50 values for the displacement of the fluorescent ligand from the ERα active site were 22, 120, and 595 nM for estradiol, raloxifene, and tamoxifen, respectively.

A review of endocrine therapy for hormone-dependent breast cancer

Purpose of the study: to provide current data on pharmacotherapy of hormone-dependent breast cancer (hdBC) and to consider the feasibility of introducing new hormone therapy drugs for breast cancer into clinical practice. Material and Methods. We analyzed 80 publications available Pubmed, Springer, Cochrane Library, etc. concerning the study of pharmacological characteristics of various groups of drugs for the treatment of hdBC, of which 49 were included in this review. Results. Currently, there are several approaches to the treatment of hdBC. Selective estrogen receptor modulators and aromatase inhibitors are the most studied and frequently used drugs. The cyclin-dependent kinase 4/6 inhibitors can be present in both the first- and second-line therapy. Currently, close attention is paid to the development of new drugs based on genomic profiling of the tumor, which is the standard of treatment for hdBC, and contributes to the personalization of therapy. Conclusion. Further development of drugs holds great promise for increasing overall survival and more accurate prognosis, response to conventional systemic therapy, and individualization of pharmacotherapy for hdBC. However, further research and development of new drugs is required. In this regard, the introduction of oral selective estrogen receptor degraders into practice and the development of new drugs that block estrogen-dependent and independent signaling to estrogen receptors are the most promising trends.

P-367 Letrozole or Tamoxifen co-administration during fertility preservation of breast cancer patients: a retrospective cohort study

Abstract Study question How do fertility preservation (FP) outcomes differ between breast cancer patients stimulated with FSH and Tamoxifen versus FSH and Letrozole? Summary answer Letrozole and Tamoxifen co-administration yielded similar number of retrieved and cryopreserved oocytes/embryos, as well as similar oocyte maturation and fertilization and rates. What is known already Oocyte/embryo cryopreservation is recommended before initiation of chemotherapy in cancer patients. The co-administration of Tamoxifen, a selective estrogen receptor modulator, or Letrozole, an aromatase inhibitor, during ovarian stimulation with gonadotropins, are used to limit the potentially harmful effects of a supra-physiological rise in estrogen levels on hormone-sensitive cancers. However, the optimal choice between the two is still unclear and with no sound evidence. Study design, size, duration Retrospective cohort study of all FP treatments of newly diagnosed breast cancer patients in two tertiary centers between 2000-2022. Collected data included 354 FP cycles of 290 patients and compared treatment parameters and outcomes of Tamoxifen or Letrozole co-administration. Participants/materials, setting, methods Breast cancer patients who underwent FP before chemotherapy were included. Patients with a history of radiation or gonadotoxic treatment, as well as those undergoing other fertility preservation treatments, such as ovarian tissue cryopreservation were excluded. Main results and the role of chance Overall, 215 Letrozole and 139 Tamoxifen treatment cycles were compared, with no significant demographic differences. Treatments with Letrozole had higher FSH dosages (3970IU vs. 2839IU, p &amp;lt; 0.001) but shorter duration (9.7 vs. 10.5 days, p &amp;lt; 0.001). The Letrozole group achieved lower peak E2 levels and endometrial thickness (1508pmol/L, 8.1mm vs. 8760pmol/L, 9.5mm, p &amp;lt; 0.001). The mean number of retrieved oocytes was comparable between the groups (13.6 with Letrozole vs 14.7 with Tamoxifen, p = 0.06). In 122 Letrozole and 46 Tamoxifen patients that underwent strictly oocytes cryopreservation the mean number of cryopreserved oocytes was comparable (11 vs. 12.1, p = 0.21). Moreover, in embryo cryopreservation cycles of 71 patients treated with Letrozole compared to 76 patients with Tamoxifen, no difference was observed in the number of cryopreserved embryos (6.2 vs. 7.0, p = 0.12). Oocyte maturation rate among strictly oocyte preservation cycles was comparable (86% with Letrozole vs. 83% with Tamoxifen, p = 0.80), as were fertilization rates in embryo cryopreservation cycles (62% vs. 63%, p = 0.8 and 71% vs. 76%, p = 0.3 in IVF and ICSI with Letrozole and Tamoxifen, respectively). Multivariate analysis, controlling for potential confounders showed no significant correlations between Tamoxifen or Letrozole co-administration and the number of retrieved oocytes or oocyte maturation rate. Limitations, reasons for caution The primary limitation of our study is its retrospective design and the variation in treatment duration and gonadotrophin dosages among groups. Wider implications of the findings This study provides reassurance that both Tamoxifen and Letrozole are equally effective options when co-administered in FP treatments of breast cancer patients. Trial registration number not applicable

The anti-aromatase and anti-estrogenic activity of plant products in the treatment of estrogen receptor-positive breast cancer

Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80 % of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.