Impact of Estrogen Receptor β on Gene Networks Regulated by Estrogen Receptor α in Breast Cancer Cells

Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Urbana, Illinois, United States
Endocrinology (Impact Factor: 4.5). 11/2006; 147(10):4831-42. DOI: 10.1210/en.2006-0563
Source: PubMed


Two subtypes of the estrogen receptor (ER), ERalpha and ERbeta, mediate the actions of estrogens, and although 70% of human breast cancers express ERbeta along with ERalpha, little is known about the possible comodulatory effects of these two ERs. To investigate this, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing different levels of ERbeta, along with their endogenous ERalpha, and have examined the effects of ERbeta and receptor occupancy, using ER subtype selective ligands, on genome-wide gene expression by microarray and pathway network analysis. ERbeta had diverse effects on gene expression, enhancing or counteracting ERalpha regulation for distinct subsets of estrogen target genes. Strikingly, ERbeta in the absence of estradiol (E2), elicited the stimulation or suppression of many genes that were normally only regulated by ERalpha with E2. In addition, ERbeta plus E2 elicited the expression of a unique group of genes that were not regulated by ERalpha plus E2 alone. The expression of genes in many functional categories were modulated by ERbeta, with the greatest numbers associated with transcription factors and signal transduction pathways. Regulation of multiple components in the TGFbeta and semaphorin pathways, and of genes controlling cell cycle progression and apoptosis, may contribute to the suppression of cell proliferation observed with ERbeta. Our observations suggest that the relative levels of ERbeta and ERalpha in breast cancers are likely to impact cell proliferation and the activities of diverse signaling pathways and their response to ER ligands and endocrine therapies.

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    • "The second ER subtype ERβ is expressed at high levels in several estrogen-targeted sites such as uterus, prostate, salivary glands, testis, ovary, bladder, colon, adipose tissue, vascular endothelium, smooth muscle, nervous and immune system [16] often together with ERα, thus contributing to ERmediated physiological responses as either homodimer or heterodimer. ERβ exerts different biological functions with respect to ERα, as confirmed by gene microarray studies from different in vitro cellular models [17] [18] as well as studies in ERβ KO mice [19]. Several cell-based studies suggest that ERβ acts as a negative modulator of ERα transcriptional activity, decreasing the sensitivity of cells to E2 [20]. "
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    ABSTRACT: Understanding of the role of Estrogen Receptors (ERα and ERβ) in the pathophysiology of breast cancer (BC) has considerably increased in last decades. Despite sharing a similar structure, these two transcription factors often exert opposite roles in BC. In addition, it has been shown that their transcriptional activity is not strictly associated to ligand activation and that unliganded ERs are able to "have a life on their own". This appears to be mainly due to ligand-independent mechanisms leading to ERs post-translational modifications or to their recruitment to specific protein complexes, dependent on cellular context. Furthermore, a significant unliganded ER activity, probably independent by the activation of other pathways, has been recently reported to affect gene transcription, microRNA expression and downstream proteome. In this review we describe recent findings on nuclear and cytoplasmic unliganded ERα and ERβ activity. We focus on functional genomics, epigenomics and interaction proteomics data, including post-transcriptional modification induced by ERs-modulated miRNAs in the BC context. A better comprehension of the molecular events controlled by unliganded ERs activity in BC pathogenesis is crucial since it may impact the therapeutic approach to the initial or acquired resistance to endocrine therapies, frequently experienced in the treatment of BC. This article is protected by copyright. All rights reserved.
    Proteomics 10/2015; DOI:10.1002/pmic.201500261 · 3.81 Impact Factor
    • "Approximately 75% of breast cancers are estrogen receptor (ER) positive (Milani et al., 2014). There are two forms of ERs, ER and ER, with distinct functions associated with: ER is more related to cell proliferation and ER is linked to cytostatic and differentiation processes (Chang et al., 2006; Rajah et al., 2009; Sotoca et al., 2008). Many breast cancer treatments, such as cisplatin (CDDP), paclitaxel (PTX) or tamoxifen (TAM) have an effect on the mitochondria, diminishing the mitochondrial functionality which results in a raise in reactive oxygen species (ROS) production and, in most cases, cell death (Andre et al., 2002; Marullo et al., 2013; Razandi et al., 2013). "
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    ABSTRACT: Breast cancer is a leading cause of death for women. The estrogen receptors (ERs) ratio is important in the maintenance of mitochondrial redox status, and higher levels of ERβ increases mitochondrial functionality, decreasing ROS production. Our aim was to determine the interaction between the ERα/ERβ ratio and the response to cytotoxic treatments such as cisplatin (CDDP), paclitaxel (PTX) and tamoxifen (TAM). Cell viability, apoptosis, autophagy, ROS production, mitochondrial membrane potential, mitochondrial mass and mitochondrial functionality were analyzed in MCF-7 (high ERα/ERβ ratio) and T47D (low ERα/ERβ ratio) breast cancer cell lines. Cell viability decreased more in MCF-7 when treated with CDDP and PTX. Apoptosis was less activated after cytotoxic treatments in T47D than in MCF-7 cells. Nevertheless, autophagy was increased more in CDDP-treated MCF-7, but less in TAM-treated cells than in T47D. CDDP treatment produced a raise in mitochondrial mass in MCF-7, as well as the citochrome c oxidase (COX) and ATP synthase protein levels, however significantly reduced COX activity. In CDDP-treated cells, the overexpression of ERβ in MCF-7 caused a reduction in apoptosis, autophagy and ROS production, leading to higher cell survival; and the silencing of ERβ in T47D cells promoted the opposite effects. In TAM-treated cells, ERβ-overexpression led to less cell viability by an increment in autophagy; and the partial knockdown of ERβ in T47D triggered an increase in ROS production and apoptosis, leading to cell death. In conclusion, ERβ expression plays an important role in the response of cancer cells to cytotoxic agents, especially for cisplatin treatment. Copyright © 2015. Published by Elsevier Ltd.
    The international journal of biochemistry & cell biology 07/2015; 66. DOI:10.1016/j.biocel.2015.07.014 · 4.05 Impact Factor
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    • "indicate partly overlapping transcriptomes induced by the two ER subtypes (Chang et al, 2006). However, experimental studies in vitro and during tumour xenograft growth have shown opposing roles of the two receptors in terms of proliferation (Ström et al, 2004; Hartman et al, 2006). "
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    ABSTRACT: Background: The expression of oestrogen receptor (ER) α characterises a subset of breast cancers associated with good response to endocrine therapy. However, the clinical significance of the second ER, ERβ1, and its splice variant ERβcx is still unclear. Methods: We here report an assessment of ERα, ERβ1 and ERβcx by immunohistochemistry using quantitative digital image analysis of 340 primary tumours and corresponding sentinel lymph nodes. Results: No differences were seen in ER levels in primary tumours vs lymph node metastases. ERβ1 and ERβcx were equally distributed among age groups and tumour histological grades. Loss of ERβ1 in the primary tumour was strongly associated with poor survival. Its prognostic impact was particularly evident in young patients and in high-grade tumours. The worst outcome was seen in the tumours lacking both ERα and ERβ1. ERβcx expression in the primary tumour correlated with a higher risk of lymph node metastasis, and with poor survival when expressed in sentinel node lymphocytes. Conclusions: Our study reveals highly significant although antagonising roles of ERβ1 and ERβcx in breast cancer. Consequently, we suggest that the histopathological assessment of ERβ1 is of value as a prognostic and potentially predictive biomarker.
    British Journal of Cancer 07/2014; 111(5). DOI:10.1038/bjc.2014.398 · 4.84 Impact Factor
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