2100

ESR2

estrogen receptor 2 (ER beta);ESR2;estrogen receptor 2 (ER beta)

estrogen receptor beta|estrogen receptor beta 4|nuclear receptor subfamily 3 group A member 2

14q23.2

protein-coding

Recent studies of ERs in breast cancer have demonstrated the existence of ERbeta in addition to ERalpha. Some clinical data indicated that ERbeta had prognostic value for patient's survival, which suggested that ERbeta plays a key role in breast cancer development and metastasis. To test this hypothesis, we generated an ERbeta high-expression cell line by reintroduced human ERbeta cDNA into MDA-MB-435 cells. We demonstrated that ERbeta exerted multiple tumor-stimulative effects on human breast carcinoma cells both in vivo and in vitro. In in vitro studies, ERbeta was able to increase the proliferation and invasion of MDA-MB-435 cells significantly, while these effects were totally estradiol independent. Also, this stimulation was characterized by downregulation of p21 and upregulation of MMP-9, as well as transcriptional factor Est-1. In in vivo studies, we also demonstrated that ERbeta-transfected MDA-MB-435 cells grew much faster and had more pulmonary metastasis than mock or wild-type cells in nude mice. In ERbeta-transfected MDA-MB-435 xenografts, ERbeta caused significant reduction in p21 protein levels. Similar effects of ERbeta on MMP-9 and Ets-1 expression noted in vitro studies were also observed in the in vivo studies. These in vitro and in vivo studies indicated that ERbeta exerted multiple stimulative effects on breast cancer development and metastasis.

PURPOSE: To assess the prognostic value of co-expression of estrogen receptor (ER)-beta and human epidermal growth factor receptor 2 (HER2) in primary breast cancer patients in China. METHODS: tumour specimens from 308 patients undergoing surgery for primary breast cancer were evaluated. expression of ER-beta and HER-2 was investigated by the immunohistochemistry. RESULTS: 123 patients (40%) were ER-beta positive and 58 (18.5 %) were HER2 positive. Among the 58 HER2 positive patients, 44 were ER-beta positive and 14 were ER-beta negative. ER-beta positive was associated with HER2 positive (75.9%, P=0.018) as well as ER-alpha positive (79.7%, P=0.023), poor cell differentiation (77.2% grade 2 or 3, P=0.010) and menopause age < 45 yr (55.3%, P=0.031). HER2 positive was associated with poor cell differentiation (93.1%, P=0.001), > or = 3 cm tumour size (67.2%, P=0.011). CONCLUSION: Both ER-beta positive and HER2 positive status was associated with poorer overall survival (OS) by univariate analysis. In both HER2 positive and HER2 negative subgroups, ER-beta positive was associated with poorer distant disease free survival (DDFS) but not OS, which implied that ER-beta might relate to metastasis in breast cancer.

ER-alpha and ER-beta genes have been proven to play a significant role in breast cancer. Epidemiologic studies have revealed that age-incidence patterns of breast cancer in Middle East differ from those in the Western countries. Two selected coding regions in the ER-beta gene (exons 3 and 7) were scanned in Iranian women with breast cancer (150) and in healthy individuals (147). PCR single-strand conformation polymorphism was performed. A site of silent single nucleotide polymorphism was found only on exon 7. The SNP was found only in breast cancer patients (5.7%) (chi2 = 17.122, P = 0.01). Codon 392 (C1176G) of allele 1 was found to have direct association with the occurrence of lymph node metastasis. Our data suggest that ER-beta polymorphism in exon 7 codon 392 (C1176G) is correlated with various aspects of breast cancer and lymph node metastasis in our group of patients.

Breast cancer is the most common cancer in women worldwide. Studies have shown that the high temperature requirement factor A3 (HtrA3) is involved in important physiological processes including maintenance of mitochondrial homeostasis, cell death, and cell signaling. HtrA3 is reported to be downregulated in several cancers and has been correlated with advancing cancer stage. We performed a retrospective study using our breast cancer tissue bank to investigate whether the expression of HtrA3 correlated with lymphatic metastasis in breast cancer and whether the expression of HtrA3 was correlated with estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 156 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of HtrA3 were measured by immunohistochemistry and western blotting. The expression of HtrA3 was lower in breast cancer. In particular, HtrA3 expression in breast cancer with lymphatic metastasis was lower than that in breast cancer without lymphatic metastasis. In breast cancers with no lymphatic metastasis, the expression of HtrA3 was lower in patients with ER- and PR-positive tumors, but when breast cancers with lymphatic metastasis were analyzed, there was no difference in HtrA3 expression between ER- and PR-positive or ER- and PR-negative tumors. These data suggest that the expression of HtrA3 was negatively correlated with lymphatic metastasis in breast cancer but not correlated with ER and PR positivity or negativity. A better understanding of the mechanism of HtrA3 may provide the basis for future development of a novel therapeutic target in breast cancer.

Colorectal cancer (CRC) is a common malignancy in both genders with a high death rate, accounting for about 56,000 each year in the USA only. In this study we examined the differences in CRC between the genders. We also looked for differences in the staining of the tumors and adjacent colonic mucosa to estrogen receptor beta1 and its possible prognostic value. Fifty-five specimens from patients who underwent resection of colon cancer in our institute were sectioned and stained for estrogen receptor beta1. The histopathological slides were evaluated for positive staining in the tumor and the normal colonic mucosa as well. The results were statistically analyzed. Positive estrogen receptor beta1 stain was found in the nuclei of the tumor cells. We noted positive stain also in the cytoplasm of the tumor cells. Similar findings were observed in the normal colonic mucosa. Statistically significant differences were found regarding the positivity of the staining between the deceased and surviving patients, men/women and those who had metastases vs. the non-metastatic ones. Our data suggest that there is an estrogen influence on the development and progression of colon cancer. Furthermore, it was found to be higher in the more severe cases.

BACKGROUND: Estrogen signaling mediated by the estrogen receptor beta (ERbeta) has potential implications in normal and abnormal prostate growth. Few studies have addressed this issue in human prostate tissue leaving conflicting results on the immunolocalization of the ERbeta in benign and neoplastic lesions. METHODS: Using a new monoclonal antibody, the current study reports on the differential expression of the ERbeta in tissue sections from 132 patients with prostate cancer. RESULTS: The prostatic epithelium expressed the ERbeta extensively in secretory luminal cell types and at lower levels in basal cells. Atrophic changes of the peripheral zone (PZ) were more immunoreactive than hyperplastic lesions of the transition zone (TZ). When compared with glandular tissue of the PZ, high-grade prostatic intraepithelial neoplasia (HGPIN) revealed decreased levels of the ERbeta in 30 of 47 cases and was unreactive in six lesions. In informative cases with suitable internal controls, all primary tumors (n = 60), lymph node (n = 7), and bone metastases (n = 5) expressed the ERbeta at variable degree. No correlation was found between the ERbeta status, the primary Gleason grade (P = 0.254), and the pathological stage (P = 0.157). Recurrent adenocarcinoma revealed markedly decreased levels in 15 of 40 cases and was ERbeta negative in five recurrent lesions. CONCLUSIONS: The secretory epithelium is a major target of ERbeta-mediated estrogen signaling in the human prostate. Its downregulation in HGPIN is consistent with chemopreventive effects that the ERbeta may exert on the prostatic epithelium. The continuous expression of the receptor protein at significant levels in untreated primary and metastatic adenocarcinoma indicates that these tumors can use estrogens through an ERbeta-mediated pathway. The partial loss of the ERbeta in recurrent tumors after androgen-deprivation may reflect the androgen-dependence of ERbeta gene expression in human prostate cancer.

Although women have an increased susceptibility to lung cancer, they also have a favorable clinical outcome. This may in part be due to female specific genetic and hormonal factors. In the present study, expression of ER-beta was investigated by immunohistochemistry using tissue samples from two cohorts: non-small cell lung cancer (NSCLC) diagnosed in 1999 in Manitoba and advanced NSCLC patients from the NCIC-CTG BR.18 trial. In the Manitoba cohort assessable tissue samples available in 79 patients (32 females and 47 males) and the majority (75%) had early stage disease. Fifty-one percent of patients expressed high levels of ER-beta (defined by >/=60, the median immunohistochemistry score) and its expression was comparable in males and females. The 3-year overall survival of the group was 53% and males had significantly worse survival compared to females (HR=2.37, 95%

BACKGROUND: Ovarian cancer is a gynecologic cancer with a high mortality rate. This shows the need of effective screening methods and reliable cancer markers for ovarian cancer staging and appropriate effective cancer treatment. METHODS: expression of estrogen receptor alpha and beta was studied by immunhistochemical analysis of 100 ovarian cancer tissue samples. RESULTS: In this study on 100 serous ovarian cancer tissue samples from patients with defined clinicopathologic features, a significant association of ER-alpha expression with ovarian cancer grading (p = 0.004), progression-free survival (p = 0.007), and cause-specific survival (p = 0.001) was demonstrated. expression of ER-beta was found to be associated with the metastatic lymph node status (p = 0.006). CONCLUSION: Immunohistochemical analysis of ER might be used as an easy, simple and highly efficient marker to identify high-risk patients and may aid in the selection of patients for a more aggressive adjuvant therapy. Furthermore, patients that show a positive ER-alpha immunostaining can be selected for a specific anti-hormonal therapy, as already performed for breast cancer patients.

The estrogen receptor (ER)beta1 is successively lost during cancer progression, whereas its splice variant, ERbeta2, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERbeta1 and/or the expression of ERbeta2 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERbeta1 or ERbeta2, we found that the ERbeta variants differentially regulate genes known to affect tumor behavior. We found that ERbeta1 repressed the expression of the bone metastasis regulator Runx2 in PC3 cells. By contrast, RUNX2 expression was up-regulated at the mRNA level by ERbeta2 in PC3 cells, whereas Slug was up-regulated by ERbeta2 in both PC3 and 22Rv1 cells. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate carcinoma, was increased by ERbeta2. In agreement with the increased Twist1 expression, we found increased expression of Dickkopf homolog 1; Dickkopf homolog 1 is a factor that has been shown to increase the RANK ligand/osteoprotegerin ratio and enhance osteoclastogenesis, indicating that the expression of ERbeta2 can cause osteolytic cancer. Furthermore, we found that only ERbeta1 inhibited proliferation, whereas ERbeta2 increased proliferation. The expression of the proliferation markers Cyclin E, c-Myc, and p45(Skp2) was differentially affected by ERbeta1 and ERbeta2 expression. In addition, nuclear beta-catenin protein and its mRNA levels were reduced by ERbeta1 expression. In conclusion, we found that ERbeta1 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERbeta2 increased proliferation and up-regulated factors involved in bone metastasis. Thus, in prostate cancer cells, ERbeta2 has oncogenic abilities that are in strong contrast to the tumor-suppressing effects of ERbeta1.

Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35-0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51-0.89, and rs4953617; OR=1.88, 95% CI: 1.21-2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18-2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26-4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis.