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We previously demonstrated that liver resection triggers estradiol production, which, in turn, induces the proliferation of hepatocytes to promote liver regeneration in mice. In this study, we demonstrated estradiol-induced estrogen receptor alpha (ERα) expression. To further explore the role of ERα in estradiol-mediated liver regeneration, in the present study, we confirmed impaired liver regeneration ability in ERα knockout mice. Further analysis during liver regeneration revealed a role for ERα in hepatic steatosis, tumor necrosis factor-alpha and interleukin 6 expression, and nuclear factor-κB and signal transducer and activator of transcription 3 DNA-binding activities. Moreover, estradiol administration accelerated liver regeneration through ERα, indicating the feasibility of the estrogen-ERα axis as a target for accelerating the rate of liver regeneration.

The objective of this study was to evaluate the expression of estrogen receptors (ER(α) and ER(β)) and androgen receptors (ARs) as prognostic factors for biochemical recurrence, disease progression and survival in patients with pT3N0M0 prostate cancer (PCa) in an urban Greek population. A total of 100 consecutive patients with pT3N0M0 PCa treated with radical prostatectomy participated in the study. The mean age and follow-up were 64.2 and 6 years, respectively. The HSCORE was used for semi-quantitative analysis of the immunoreactivity of the receptors. The prognostic value of the ER(α) and ER(β) and AR was assessed in terms of recurrence, progression, and survival. AR expression was not associated with any of the above parameters; however, both ERs correlated with the prognosis. A univariate Cox regression analysis showed that ER(α) positive staining was significantly associated with a greater hazard for all outcomes. Increased ER(β) staining was significantly associated with a lower hazard for all outcomes in the univariate analysis. When both ER HSCORES were used for the analysis, it was found that patients with high ER(α) or low ER(β) HSCORES compared with patients with negatively stained ER(α) and >1.7 hSCORE ER(β) had 6.03, 10.93, and 10.53 times greater hazard for biochemical disease recurrence, progression of disease and death, respectively. Multiple Cox proportional hazard analyses showed that the age, preoperative prostate specific antigen, Gleason score and ERs were independent predictors of all outcomes. ER expression is an important prognosticator after radical prostatectomy in patients with pT3N0M0 PCa. By contrast, AR expression has limited prognostic value.

The endocrine system of animals consists of fine-tuned self-regulating mechanisms that maintain the hormonal and neuronal milieu during tissue development. This complex system can be influenced by endocrine disruptors (ED)—substances that can alter the hormonal regulation even in small concentrations. By now, thousands of substances—either synthesized by the plastic, cosmetic, agricultural, or medical industry or occurring naturally in plants or in polluted groundwater—can act as EDs. Their identification and testing has been a hard-to-solve problem; Recent indications that the ED effects may be species-specific just further complicated the determination of biological ED effects. Here we compare the effects of bisphenol-A, zearalenone, and arsenic (well-known EDs) exerted on mouse and rat neural cell cultures by measuring the differences of the ED-affected neural estrogen- and thyroid receptors. EDs alters the receptor expression in a species-like manner detectable in the magnitude as well as in the nature of biological responses. It is concluded that the interspecies differences (or species specificity) in ED effects should be considered in the future testing of ED effects.

It has been shown that citrus flavanone naringenin and its prenyl derivative 8-prenylnaringenin (8-PN) possess various pharmacological activities in in vitro and in vivo models. Interestingly, it has been proposed that prenylation can enhance biological potentials, including the estrogen-like activities of flavonoids. The objective of this study was to investigate the anti-diabetic potential and molecular mechanism of 8-PN in streptozotocin (STZ)-induced insulin-deficient diabetic mice in comparison with naringenin reported to exhibit hypoglycemic effects. The oral administration of naringenin and 8-PN ameliorated impaired glucose homeostasis and islet dysfunction induced by STZ treatment. These protective effects were associated with the suppression of pancreatic β-cell apoptosis and inflammatory responses in mice. Moreover, both naringenin and 8-PN normalized STZ-induced insulin-signaling defects in skeletal muscles and apoptotic protein expression in the liver. Importantly, 8-PN increased the protein expression levels of estrogen receptor-α (ERα) in the pancreas and liver and of fibroblast growth factor 21 in the liver, suggesting that 8-PN could act as an ERα agonist in the regulation of glucose homeostasis. This study provides novel insights into the mechanisms underlying preventive effects of naringenin and 8-PN on the impairment of glucose homeostasis in insulin-deficient diabetic mice.

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.

Female astronauts on deep-space missions are at increased risk of breast cancer due to exposure to galactic cosmic radiation (GCR). This study aimed to understand how GCR might lead to breast cancer by focusing on a hormone-related pathway involving estrogen receptor alpha (ERα) and other related molecules (ERRα and SPP1). In mice exposed to simulated GCR, we observed increased levels of estrogen, changes in breast tissue growth, and activation of genes that promote tumor formation. Similar results were found when analyzing human breast cancer tissues, suggesting that this pathway is also important in human breast cancer. These findings highlight the ERα-ERRα-SPP1 pathway as a key player in radiation-induced breast cancer risk, providing a potential target for developing protective therapies to safeguard female astronauts during deep-space missions.

Estrogen receptors in prostate cancer (PCa) are a subject of debate. The aim of the present study was to investigate whether estrogen receptor-α (ERα) and estrogen receptor-β (ERβ) impact the biochemical recurrence (BCR) of non-metastatic PCa after surgery. Following the application of the exclusion criteria, data from 108 patients who underwent laparoscopic radical prostatectomy between January 2011 and December 2019 were retrospectively evaluated. A total of 36 patients with BCR constituted the BCR group. The control group was formed using the Propensity Score Matching (PSM) method with a 1:2 ratio, including parameters with well-studied effects on BCR. The median follow-up time was 74.3 (range, 30-127.5) months in the BCR group and 66.6 (range, 31.5-130) months in the control group. Pathology specimens from the two groups were immunohistochemically stained with ERα and ERβ antibodies. Logistic regression analysis and survival analysis were performed. No differences in clinicopathological characteristics were detected between the two groups. The patients with ERα(−)/ERβ(+) staining results had a significantly fewer BCRs than other patients (P=0.024). In the logistic regression analysis, patients with ERα(−)/ERβ(+) PCa also had a significantly lower risk of recurrence (P=0.048). In the survival analysis, the 5-year BCR-free survival rate of patients with ERα(−)/ERβ(+) PCa was higher than that of other patients (85.7 vs. 66.1%; P=0.031). Excluding the effects of well-studied risk factors for recurrence by the PSM method, the present study showed that ERα and ERβ have prognostic value for non-metastatic PCa. The 5-year BCR-free survival rate is significantly higher in patients whose PCa tissue has ERα(−)/ERβ(+) staining results.

The platelet-derived growth factor (PDGF) family, a complex and imperative group of proangiogenic factors, acts as strong cell growth chemokines and is essential for the progression of malignancy in humans. In the present study, it was observed that aberrant PDGFB expression is associated with survival rates in patients with estrogen receptor-positive (ER+) breast cancer unlike other subtypes, including PDGFA, PDGFC and PDGFD. Accordingly, the effect of specific PDGF receptor (PDGFR) inhibitors on ER-α+ breast cancer cells was investigated. To block the PDGF-BB signaling pathway, PDGFR inhibitors (sunitinib or ponatinib) were employed. Sunitinib and ponatinib were found to arrest the cell cycle at the G0-G1 phase. In addition, the two PDGFR inhibitors were revealed to significantly inhibit cell growth and decrease the expression of matrix metalloproteinase-1, which is one of the metastasis-related genes. Finally, the combined effects of the two PDGFR inhibitors with tamoxifen were investigated. The results demonstrated that the combination of two PDGFR inhibitors with tamoxifen inhibited the growth of cells more consistently, compared with the effect mediated by tamoxifen alone. Therefore, it is proposed that PDGFR inhibitors, including sunitinib and ponatinib, should be applied effectively to treat ER-α+ breast cancer.

Evidence shows that women have lower tumour necrosis factor‐α (TNF‐α) levels and lower incidences of heart dysfunction and sepsis‐related morbidity and mortality. To identify the cardioprotective effects and precise cellular/molecular mechanisms behind estrogen and estrogen receptors (ERs), we investigated the effects of 17β‐estradiol (E2) and estrogen receptor α (ERα) on LPS‐induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)‐inducible Tet‐On/ERα H9c2 myocardial cells and ERα‐transfected primary cardiomyocytes overexpressing ERα. We found that LPS challenge activated JNK1/2, and then induced IκB degradation, NFκB activation, TNF‐α up‐regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E2, membrane‐impermeable BSA‐E2 and/or Dox, which induces ERα overexpression, significantly inhibited LPS‐induced apoptosis by suppressing LPS‐up‐regulated JNK1/2 activity, IκB degradation, NFκB activation and pro‐apoptotic proteins (e.g. TNF‐α, active caspases‐8, t‐Bid, Bax, released cytochrome c, active caspase‐9, active caspase‐3) in myocardial cells. However, the cardioprotective properties of E2, BSA‐E2 and ERα overexpression to inhibit LPS‐induced apoptosis and promote cell survival were attenuated by applying LY294002 (PI3K inhibitor) and PI3K siRNA. These findings suggest that E2, BSA‐E2 and ERα expression exert their cardioprotective effects by inhibiting JNK1/2‐mediated LPS‐induced TNF‐α expression and cardiomyocyte apoptosis through activation of Akt.