The aim of the present study was to investigate the association between the expression levels of estrogen receptor (ER)β and the curative effect of endocrine therapy in breast cancer patients. Cancer tissues were collected from 583 breast cancer patients between January 2000 and December 2010 and used for analysis. ERβ expression levels were determined using immunohistochemical staining. The Kaplan-Meier method was used for survival analysis and the log-rank test was conducted for difference analysis between survival times. In addition, Cox multivariate analysis was performed to analyze prognostic factors for breast cancer. In the immunohistochemical staining assay, a positive ERβ expression rate of <10% was defined as ERβ low expression, while >10% was defined as ERβ high expression. In patients expressing low levels of ERβ, the median tumor-free survival time of the patients who received endocrine therapy was significantly higher compared with that of the patients who did not receive endocrine therapy. By contrast, in patients with high ERβ expression levels, there was no significant difference in the median tumor-free survival time between the patients who received endocrine therapy and those who did not. In addition, compared with ERβ low expression patients, ERβ high expression patients had a significantly lower median tumor-free survival time. Furthermore, ERβ expression, human epidermal growth factor receptor 2 expression, tumor size, lymph node metastasis, postoperative chemotherapy, radiotherapy and endocrine therapy were identified to be independent prognostic factors for breast cancer. Therefore, high ERβ expression in breast cancer indicates poor prognosis for endocrine therapy.

Endometriosis is an estrogen-dependent inflammatory disorder characterized by the presence of endometrial tissue outside the uterine cavity. Patients experience chronic pelvic pain and infertility, with the most likely origin of the tissue deposits (lesions) being endometrial fragments shed at menses. Menstruation is an inflammatory process associated with a dramatic increase in inflammatory mediators and tissue-resident immune cells. In the present study, we developed and validated a mouse model of endometriosis using syngeneic menstrual endometrial tissue introduced into the peritoneum of immunocompetent mice. We demonstrate the establishment of endometriotic lesions that exhibit similarities to those recovered from patients undergoing laparoscopy. Specifically, in both cases, lesions had epithelial (cytokeratin+) and stromal (vimentin/CD10+) cell compartments with a well-developed vasculature (CD31+ endothelial cells). Expression of estrogen receptor Î² was increased in lesions compared with the peritoneum or eutopic endometrium. By performing experiments using mice with green fluorescent protein-labeled macrophages (MacGreen) in reciprocal transfers with wild-type mice, we obtained evidence that macrophages present in the peritoneum and in menses endometrium can contribute to the inflammatory microenvironment of the lesions. In summary, we developed a mouse model of endometriosis that exhibits similarities to human peritoneal lesions with respect to estrogen receptor expression, inflammation, and macrophage infiltration, providing an opportunity for further studies and the possible identification of novel therapies for this perplexing disorder.

Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

In women, the risk for cerebral ischemia climbs rapidly after menopause. At menopause, production of ovarian hormones; i.e., progesterone and estrogen, slowly diminishes. Estrogenhas been suggested to confer natural protection to premenopausal women from ischemic stroke and some of its debilitating consequences. This notion is also strongly supported by laboratory studies showing that a continuous chronic 17β-estradiol (E2; a potent estrogen) regimen protects brain from ischemic injury. However, concerns regarding the safety of the continuous intake of E2 were raised by the failed translation to the clinic. Recent studies demonstrated that repetitive periodic E2 pretreatments, in contrast to continuous E2 treatment, provided neuroprotection against cerebral ischemia in ovariectomized rats. Periodic E2pretreatment protects hippocampal neurons through activation of estrogen receptor subtypebeta (ER-β). Apart from neuroprotection, periodic activation of ER-β in ovariectomized rats significantly improves hippocampus-dependent learning and memory. Difficulties in learning and memory loss are the major consequence of ischemic brain damage. Periodic ER-β agonist pretreatment may provide pharmacological access to a protective state against ischemic stroke and its debilitating consequences. The use of ER-β-selective agonists constitutes a safer target for future research than ER-α agonist or E2, inasmuch as it lacks the ability to stimulate the proliferation of breast or endometrial tissue. In this review, we highlight ER-β signaling as a guide for future translational research to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women, while avoiding the side effects produced by chronic E2 treatment.

Vav1, a guanine nucleotide exchange factor (GEF) for Rho family GTPases, is a hematopoietic protein involved in a variety of cellular events. In recent years, aberrant expression of Vav1 has been reported in non-hematopoietic cancers including human breast cancer. It remains to be answered how Vav1 is expressed and what Vav1 does in its non-resident tissues. In this study, we aimed to explore the mechanism for Vav1 expression in breast cancer cells in correlation with estrogen-ER pathway. We not only verified the ectopic expression of Vav1 in human breast cancer cell lines, but also observed that Vav1 expression was induced by 17β-estradiol (E2), a typical estrogen receptor (ER) ligand, in ER-positive cell lines. On the other hand, Tamoxifen, a selective estrogen receptor modulator (SERM), and ICI 182,780, an ER antagonist, suppressed the expression of Vav1. The estrogen receptor modulating Vav1 expression was identified to be α form, not β. Furthermore, treatment of E2 increased the transcription of vav1 gene by enhancing the promoter activity, though there was no recognizable estrogen response element (ERE). Nevertheless, two regions at the vav1 gene promoter were defined to be responsible for E2-induced activation of vav1 promoter. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) analyses suggested that ERα might access to the vav1 promoter via interacting with transcription factors, c-Myb and ELF-1. Consequently, the enhanced expression of Vav1 led to the elevation of Cyclin D1 and the progression of cell cycle. The present study implies that estrogen-ER modulates the transcription and expression of Vav1, which may contribute to the proliferation of cancerous cells.

BACKGROUND:

The incidence of papillary thyroid cancer (PTC) is markedly higher in women than men during the reproductive years. In vitro studies have suggested that estrogen may play an important role in the development and progression of PTC through estrogen receptors (ERs). This study aimed to investigate the expression patterns of the two main ER subtypes, α and β1 (wild-type ERβ), in PTC tissue and their clinical significance.

METHODS:

Immunohistochemical staining of thyroid tissue sections was performed to detect ER expression in female patients with PTC (n =”‰89) and nodular thyroid goiter (NTG; n =”‰30) using the Elivision™ plus two-step system. The relationships between ER subtype expression and clinicopathological/biological factors were further analyzed.

RESULTS:

The positive percentage and expression levels of ERα were significantly higher in female PTC patients of reproductive age (18-45 years old; n =”‰50) than age-matched female NTG patients (n =”‰30), while ERβ1 exhibited the opposite pattern. There was no difference in ERα or ERβ1 expression between female PTC patients of reproductive age and those of advanced reproductive age (>45 years old; n =”‰39). In the female PTC patients of reproductive age, ERα expression level was positively correlated with that of Ki-67, while ERβ1 was negatively correlated with mutant P53. Furthermore, more patients with exclusively nuclear ERα expression had extrathyroidal extension (ETE) as compared with those with extranuclear ERα localization. VEGF expression was significantly decreased in female PTC patients of reproductive age with only nuclear ERβ1 expression when compared with those with extranuclear ERβ1 localization. In PTC patients of advanced reproductive age, neither ERα nor ERβ1 expression showed any correlation with that of Ki-67, mutant P53, VEGF, tumor size, TNM stage, ETE, or lymph node metastases.

CONCLUSIONS:

The differential expression patterns of the two ER subtypes between PTC and NTG indicate that ERα may be a useful immunohistochemical marker for differential diagnosis of PTC. The associations of ER subtype expression with Ki-67, mutant P53, VEGF expression and ETE in female PTC patients of reproductive age suggest that estrogen-activated ERα may mediate stimulatory effects on PTC growth and progression whereas ERβ1 has some inhibitory actions.

Estrogen deficiency in menopausal women is the main cause of osteoporosis. Phytoestrogen could be a suitable candidate for treatment of post-menopausal osteoporosis. Recent studies showed that S. chinensis contains several lignans, which may be phytoestrogen. In this study, we investigated the ameliorative effects of S. chinensis on post-menopausal osteoporosis. 30% ethanol extract of S. chinensis (SC) was administered orally for 6 weeks after 7 weeks of ovariectomized-induced osteoporosis. Bone mineral density was significantly increased following increased serum osteocalcin levels by SC treatment. Histological analysis showed that SC reduced the increased growth plate of the epiphyseal plate in femur. In addition, pores within bone marrow cells filling the lateral and medial epicondyle were decreased. Serum estradiol concentration was significantly increased in the SC-treated group. The expressions ofestrogen receptor-α and -β were increased in uterus and MCF-7 breast cancer cells by SC treatment. And two transcriptions of proto-oncogenes, c-fos and c-Jun, were suppressed by treatment of SC. From these data, we propose that S. chinensis attenuates post-menopausal osteoporosis with its phytoestrogenic effects. S. chinensis may have the potential to be used as an alternative for treatment of osteoporosis.

Prostate cancer (PC) progression from androgen-dependent (AD) to castration-resistant (CR) disease is a process caused by modifications of different signal transduction pathways within tumor microenvironment. Reducing cell proliferation, estrogen receptor beta (ERbeta) is emerging as a potential target in PC chemoprevention. Among the known selective ERbeta ligands, 3beta-Adiol, the endogenous ligand in the prostate, has been proved to counteract PC progression. This study compares the effects of chronic exposure (1-12 weeks) to different ERbeta selective ligands (DPN, 8beta-VE2, 3beta-Adiol) on proliferation of human androgen-responsive CWR22Rv1 cells, representing an intermediate phenotype between the AD- and CR-PC. 3beta-Adiol (10 nM) is the sole ligand decreasing cell proliferation and increasing p21 levels. In vitro transcriptional activity assays were performed to elucidate different behavior between 3beta-Adiol and the other ligands; in these experiments the endogenous and the main ERbeta subtype activation were considered. It is concluded that ERbeta activation has positive effects also in androgen-responsive PC. The underlying mechanisms are still to be clarified and may include the interplay among different ERbeta subtypes and the specific PC microenvironment. ERbeta agonists might be useful in counteracting PC progression, although the final outcome may depend upon the molecular pattern specific to each PC lesion.