Estrogen Receptor Alpha Variant Research Articles

Estrogen receptor beta (ESR2) gene polymorphism and susceptibility to dementia.

Strong evidence supports the involvement of sex steroid hormones in the development and progression of dementia. Attention has been largely focused on the association between genetic variants of estrogen receptor alpha (ERα, ESR1) with dementia, although several studies indicate that ERβ is predominantly expressed in the brain. Interestingly, however, a limited number of studies evaluate the role of ERβ (ESR2) in dementia. Therefore, a meta-analysis was conducted to clarify the association between ESR2 genetic polymorphisms and the risk of dementia. All the relevant studies evaluating ESR2 genetic polymorphisms and dementia were identified through online databases. In total, 14 studies including 20,609 subjects were analyzed. Collectively, it was found that a combined data set of ESR2 polymorphisms was not associated with dementia risk. Interestingly, ESR2 rs4986938 polymorphism is significantly associated with dementia in the Asian population (OR = 0.73, 95% CI 0.59-0.91, P = 0.006). The carrier of A allele in rs4986938 exhibits a protective effect against dementia (A vs. G, OR = 0.6633, P = 0.012; AA + GA vs. GG, OR = 0.6499, P = 0.014; GA vs. AA + GG, OR = 0.6672, P = 0.025; GA vs. GG, OR = 0.6617, P = 0.022). In conclusion, our study suggests that ESR2 genetic polymorphisms are not significantly associated with dementia risk. ESR2 rs4986938 may have potential as a genetic marker for dementia in the Asian population. However, further studies need to verify this conclusion.

2 - Estrogen receptor alpha variants as possible markers of prostate cancer development and progression

2 - Estrogen receptor alpha variants as possible markers of prostate cancer development and progression

P3.01-044 Splicing Variant of Estrogen Receptor Alpha is Associated with Pathological Invasiveness in Smoking Independent Lung Cancer: Topic: Functional Biology in Lung Cancer

P3.01-044 Splicing Variant of Estrogen Receptor Alpha is Associated with Pathological Invasiveness in Smoking Independent Lung Cancer: Topic: Functional Biology in Lung Cancer

Allelic variants of estrogen receptor alpha and their association with prostate cancer risk in Slovak population

Allelic variants of estrogen receptor alpha and their association with prostate cancer risk in Slovak population

From ERα66 to ERα36: a generic method for validating a prognosis marker of breast tumor progression.

BackgroundEstrogen receptor alpha36 (ERalpha36), a variant of estrogen receptor alpha (ER) is expressed in about half of breast tumors, independently of the [ER+]/[ER-] status. In vitro, ERalpha36 triggers mitogenic non-genomic signaling and migration ability in response to 17beta-estradiol and tamoxifen. In vivo, highly ERalpha36 expressing tumors are of poor outcome especially as [ER+] tumors are submitted to tamoxifen treatment which, in turn, enhances ERalpha36 expression.ResultsOur study aimed to validate ERalpha36 expression as a reliable prognostic factor for cancer progression from an estrogen dependent proliferative tumor toward an estrogen dispensable metastatic disease. In a retrospective study, we tried to decipher underlying mechanisms of cancer progression by using an original modeling of the relationships between ERalpha36, other estrogen and growth factor receptors and metastatic marker expression. Nonlinear correlation analyses and mutual information computations led to characterize a complex network connecting ERalpha36 to either non-genomic estrogen signaling or to metastatic process.ConclusionsThis study identifies ERalpha36 expression level as a relevant classifier which should be taken into account for breast tumors clinical characterization and [ER+] tumor treatment orientation, using a generic approach for the rapid, cheap and relevant evaluation of any candidate gene expression as a predictor of a complex biological process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0178-7) contains supplementary material, which is available to authorized users.

ER-α36: a novel biomarker and potential therapeutic target in breast cancer.

Estrogen receptor-alpha36 (ER-α36) is a 36-kDa variant of estrogen receptor-alpha (ER-α) firstly identified and cloned by Wang et al in 2005. It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-α (ER-α66). ER-α36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway. Additionally, it inhibits the traditional genomic signaling pathway mediated by ER-α66 in a dominant-negative pattern. Accumulating evidence has demonstrated that ER-α36 regulates the physiological function of various tissues. Thus, dysregulation of ER-α36 is closely associated with plenty of diseases including cancers. ER-α36 is recognized as a molecular abnormality which solidly correlates to carcinogenesis, aggressiveness, and therapeutic response of breast cancer. Additionally, special attention has been paid to the role of ER-α36 in endocrine therapy resistance. Therefore, ER-α36 provides a novel biomarker of great value for diagnosis, prognosis, and treatment of breast cancer. It may also be a potential therapeutic target for breast cancer patients, especially for those who are resistant to endocrine therapy. In this review, we will overview and update the biological characteristics, underlying mechanism, and function of ER-α36, focusing on its biological function in breast cancer and endocrine therapy resistance. We will evaluate its application value in clinical practice.

The elevated level of ERα36 is correlated with nodal metastasis and poor prognosis in lung adenocarcinoma

IntroductionERα36 is a recently cloned variant of estrogen receptor-alpha which has been proved to play an active role in a series of malignant diseases. MethodERα36 expression was examined using immunohistochemical methods with sections from 126 resected NSCLC specimens. The immunoreactivity of ERα66 was also studied as a comparison. Kaplan–Meier method and multivariable Cox proportional hazards regression analyses were used to examine the relationship between ERα36 and survival. ResultERα36 was more highly expressed in NSCLC patients compared to ERα66. ERα36 expression has a strong correlation with histology (AC: 53/70, SCC: 16/56, P<0.000) and had a significantly positive correlation with lymphatic metastasis (P=0.014) in adenocarcinoma. High ERα36 expression was correlated with poorer overall survival (OS) (P=0.020) and disease-free survival (DFS) (P=0.024) in adenocarcinoma. Furthermore, ERα36 status was a significant independent prognostic factor of OS (P=0.018, HR: 3.142, 95% CI: 1.215–8.128) and DFS (P=0.024, HR: 2.720, 95% CI: 1.141–6.486) in lung adenocarcinoma patients. ConclusionERα36 had a high expression mainly in adenocarcinoma and the high expression of ERα36 was strongly correlated with more advanced regional lymph node metastasis and poor survival in lung adenocarcinoma.

17Beta-Estradiol Promotes Aggressive Laryngeal Cancer Through Membrane-Associated Estrogen Receptor-Alpha 36

17β-estradiol (E2) plays a key role in tumorigenesis by enhancing cell survivability and metastasis through its cytoplasmic receptors. Recently, a variant of estrogen receptor alpha, ERα36 has been implicated as a substantial mediator of E2's proliferative and antiapoptotic effects through rapid membrane-associated signaling, and cancers previously regarded as hormone-independent due to the absence of traditional receptors, may in fact be susceptible to E2. Despite rising from a secondary sex organ and having a clear gender disposition, laryngeal cancer is not uniformly accepted as hormone dependent, even in the face of compelling evidence of E2 responsiveness. The aim of this study was to further elucidate the role of E2 in the tumorigenesis of laryngeal cancer, both in vitro and in vivo. ERα36 presence was evaluated in membranes of the laryngeal carcinoma cell line, Hep2, as well as in laryngeal tumor samples. In vitro ERα36 was found to mediate rapid activation of protein kinase C and phospholipase D by E2, leading to increased proliferation and protection against chemotherapy-induced apoptosis. Furthermore, in response to E2 activation of ERα36, an upregulation of angiogenic and metastatic factors was observed. Clinical analysis of laryngeal tumors revealed a similar association between the amount of ERα36 and VEGF and indicated a role in lymph node metastasis. These findings present compelling evidence of ERα36-dependent E2 signaling in laryngeal cancer. Thus, targeting ERα36 may reduce the deleterious effects of E2 in laryngeal cancer, ultimately suggesting the importance of antiestrogen therapy or the production of novel drugs that specifically target ERα36.

Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol

ERΔ3 transgenic mice expressing a dominant negative estrogen receptor α (ERα) variant lacking the second zinc finger in the DNA binding domain were developed to examine its potential to inhibit estrogen action in vivo. To investigate if ERΔ3 expression influences uterine carcinogenesis, ERΔ3 transgenic mice were exposed to diethylstilbestrol (DES) on post-natal days 1–5. Neonatal DES treatment induced uterine adenocarcinomas in 81% of 8-month-old ERΔ3 mice compared to 49% of wild-type females (p<0.016). ERΔ3 did not inhibit the expression of the estrogen-responsive progesterone receptor and lactoferrin genes in the presence of ERα or modify their expression in ERα knockout (αERKO) mice. Higher circulating 17β-estradiol levels and non-classical signaling by ERΔ3 may be related to the earlier incidence of uterine cancer. These findings indicate that expression of this ERα variant can influence determining events in uterine cancer development and its natural occurrence in the human uterus would unlikely be protective.

Differentiated expression level of mRNA variants of estrogen receptor alpha with alternative promoters in immune cells stimulated with cytokines

Differentiated expression level of mRNA variants of estrogen receptor alpha with alternative promoters in immune cells stimulated with cytokines

Caveolin-1 gene silencing promotes the activation of PI3K/AKT dependent on Erα36 and the transformation of MCF10ACE

ERalpha36, a variant of estrogen receptor-alpha, acts as a dominant-negative factor in both estrogen-dependent and estrogenindependent transactivation signaling pathways, and is a key factor in the promotion, progression and prognosis of breast cancers. Caveolin-1, a 22- to 24-kD integral membrane protein, may function as a tumor suppressor in inhibiting of many growth-promoting signaling pathways. It was shown that downregulation of Caveolin-1 strengthens the interaction of ERalpha and Caveolin-1. In conclusion, Caveolin-1 gene silencing activated the PI3K/AKT signaling pathway in an ERalpha36-dependent way. Our finding may provide a promising therapeutic target of breast cancer.

Transcriptional analysis of estrogen receptor alpha variant mRNAs in colorectal cancers and their matched normal colorectal tissues

Estrogen is involved in suppression of colorectal cancer development and exerts its function via estrogen receptors α, β and their splicing variants. Whether the recently indentified ER-α splicing variants, ER-α36 and ER-α46, play a role in colorectal cancer development is unknown. In this study, we quantified the mRNA copy numbers of wild type ER-α (ER-α66), ER-α46 and ER-α36 in 35 colorectal cancers and their matched normal colorectal tissues by quantitative real-time PCR assay, and correlated their mRNA levels with the clinicopathological properties of the tumors. We found that ER-α66, ER-α46 and ER-α36 mRNAs were coexpressed in all colorectal cancers and their matched normal tissues. The decreased mRNA levels of ER-α36 and ER-α46 whereas no difference of ER-α66 mRNA was observed in colorectal cancers compared to their matched normal tissues. Moreover, change in the expression of ER-α36 mRNA level was correlated with Dukes’ stage of the tumor and the lymph node metastasis. ER-α36 mRNA was decreased significantly in Dukes’ C + D compared to Dukes’ A + B stage tumors ( P = 0.017), and the expression of ER-α36 mRNA in N 1/N 2 was lower than that in N 0 lymph node metastasis ( P = 0.049). So ER-α36 and ER-α46 might be implicated in the development and progression of colorectal cancers.

Estrogen receptor gene 1 variants are not associated with suicidal behavior

Estrogen is thought to be involved in the pathophysiology of depression and suicidal behaviors. We studied gene variants of estrogen receptor alpha (rs827421, rs1913474, rs1801132, rs722207, rs974276 and rs910416) in 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 German individuals who committed suicide and 312 German healthy subjects. Single markers and haplotype analysis in relation to suicidal behaviors (suicide attempters/completers) did not reveal any significant association. These were also not associated with related features, such as violence or impulsivity of suicide attempt, State-Trait Anger Expression Inventory (STAXI) and Questionnaire for Measuring Factors of Aggression (FAF) scores. In conclusion, our study does not support the hypothesis that estrogen receptor alpha gene variants are major contributors to suicide or to anger- or aggression-related behaviors.

Identification of estrogen receptor alpha variants in breast tumors: Implications for predicting response to hormonal therapies

Identification of estrogen receptor alpha variants in breast tumors: Implications for predicting response to hormonal therapies

Expression of an estrogen receptor alpha variant protein in cell lines and tumors

Human estrogen receptor alpha (ER) mRNA is a mixture of wild type and alternatively spliced variants. Many studies have examined the potential of ER mRNA profiles to serve as diagnostic/prognostic cancer biomarkers, but only a few have attempted to correlate ER mRNA profiles with protein expression. Representative ER mRNA pools were reproduced from the cDNAs of MCF-7 cells, a human breast tumor and human uterus and translated in a protease-free environment by reticulocyte lysates to determine relative translation efficiencies between the various ER mRNA transcripts and to facilitate identification of translated proteins. Cell line and tumor extracts were then examined for expression of the ER variant proteins identified in reticulocyte lysate translations. Each of the ER mRNA pools were translated by reticulocyte lysates into two ER proteins with molecular weights of ≈60 and 52 kD. Western immunoblotting with various C- and N-terminal-directed, anti-ER antibodies and comparison with expressed ER protein standards established that the 52 kD protein (ERΔ7P) was translated from the predominant splice variant mRNA in each pool, which is missing exon 7. The 60 kD protein contained wild type ER sequence minus 61 C-terminal amino acids lost due to an intentional run off truncation. ERΔ7P expression was subsequently demonstrated in MCF-7 cells by Western immunoblotting with the site-directed antibodies. A protein corresponding to ERΔ7P was also detected in other ER positive breast tumor cell lines, and extracts of ER positive breast and uterine tumors. This widespread expression of ERΔ7P in vivo suggests that it may have some biological function. ERΔ7P may also affect immunohistochemical evaluation of ER positivity in tumors depending upon the level of its expression and the antibody used.

The truncated estrogen receptor alpha variant lacking exon 5 is not involved in progesterone receptor expression in meningiomas

Human meningioma tissues are mostly estrogen receptor (ER) negative and progesterone receptor (PR) positive in ligand binding and enzyme immuno assays. To explain this apparently ER independent PR expression, we investigated the existence of a ‘hidden’ ER variant, which would be capable of activating transcription of the PR gene. Total RNA of seven meningiomas, two breast cancer tissues and of MCF7 cells was analyzed by RT-PCR using primers situated in exon 4 and exon 6. Differential hybridization of the PCR transcripts with probes in exon 4 and 5 respectively, revealed a wild type ER (wtER) fragment and an exon 5 deleted ER variant (ERΔ5). PCR products of two meningiomas were cloned for sequence analysis. The result confirmed the existence of a wtER and ERΔ5. RT-PCR followed by Southern analysis was performed on mRNA of 23 meningiomas to determine the amount of ERΔ5 relative to wtER, which was compared to the PR content of the tissues. In contrast to our initial hypothesis and literature data on breast cancer, there was no relationship between the ERΔ5/wtER ratio and PR protein concentration. It is therefore concluded that ERΔ5 mRNA does not play the dominant role in PR synthesis in meningioma tissue.