The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

Chantalat, Élodie; Boudou, Frédéric; Laurell, Henrik; Palierne, Gaëlle; Houtman, René; Melchers, Diana; Rochaix, Philippe; Filleron, Thomas; Stella, Alexandre; Burlet‐Schiltz, Odile; Brouchet, A.; Flouriot, Gilles; Métivier, Raphaël; Arnal, Jean‐François; Fontaine, Coralie; Lenfant, Françoise

doi:10.1186/s13058-016-0780-7

Cited by 55 publications

(48 citation statements)

References 52 publications

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“…In addition, a specific isoform of ERα, ERα-36, is overexpressed in HCC [ 73 ]. Estrogen stimulates HCC cells growth through ERα-36 [ 74 ]. Therefore, variance in ERα subtypes and isoforms may dictate the response of HCC to estrogen.…”

Section: Expression Of Er In Human Tumorsmentioning

confidence: 99%

Mechanisms for estrogen receptor expression in human cancer

et al. 2018

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Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling and brain functions. However, estrogen also promotes mammary, ovarian and endometrial tumorigenesis. Estrogen antagonists and drugs that reduce estrogen biosynthesis have become highly successful therapeutic agents for breast cancer patients. The effects of estrogen are largely mediated by estrogen receptor (ER) α and ERβ, which are members of the nuclear receptor superfamily of transcription factors. The mechanisms underlying the aberrant expression of ER in breast cancer and other types of human tumors are complex, involving considerable alternative splicing of ERα and ERβ, transcription factors, epigenetic and post-transcriptional regulation of ER expression. Elucidation of mechanisms for ER expression may not only help understand cancer progression and evolution, but also shed light on overcoming endocrine therapy resistance. Herein, we review the complex mechanisms for regulating ER expression in human cancer.

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Section: Expression Of Er In Human Tumorsmentioning

confidence: 99%

Mechanisms for estrogen receptor expression in human cancer

et al. 2018

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“…The importance of AF1 is further supported by the existence, beside the “classic” and most abundant full-length 66 kDa ERα (ERα66), of another ERα isoform of 46 kDa (ERα46) which lacks the A/B domain and consequently AF-1. This isoform is expressed in various cell types, in particular endothelial cells [78] , but also in most breast tumors [79] . It can be generated by either alternative splicing, proteolysis or translation through an internal ribosome entry site (IRES) [79] , but its physiological role is still unknown.…”

Section: Contribution Of Erα Nuclear Effects To Metabolic and Vasculamentioning

confidence: 99%

“…This isoform is expressed in various cell types, in particular endothelial cells [78] , but also in most breast tumors [79] . It can be generated by either alternative splicing, proteolysis or translation through an internal ribosome entry site (IRES) [79] , but its physiological role is still unknown.…”

Section: Contribution Of Erα Nuclear Effects To Metabolic and Vasculamentioning

confidence: 99%

Estrogen receptor subcellular localization and cardiometabolism

Gourdy

Guillaume

Fontaine

et al. 2018

Molecular Metabolism

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BackgroundIn addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ERα was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ERαAF-1 and ERαAF-2). However, besides these nuclear actions, a pool of ERα is localized in the vicinity of the plasma membrane, where it mediates rapid signaling effects called membrane-initiated steroid signals (MISS) that have been well described in vitro, especially in endothelial cells.Scope of the reviewThis review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ERα activation that contribute to the cardiometabolic protection conferred by estrogens. Indeed, new transgenic mouse models (affecting either DNA binding, activation functions or membrane localization), together with the use of novel pharmacological tools that electively activate membrane ERα effects recently allowed to begin to unravel the different modes of ERα signaling in vivo.ConclusionAltogether, available data demonstrate the prominent role of ERα nuclear effects, and, more specifically, of ERαAF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ERα signaling selectively mediates some of the estrogen endothelial/vascular effects (NO release, reendothelialization) and could also contribute to the regulation of energy balance, insulin sensitivity, and glucose metabolism. Such a dissection of ERα biological functions related to its subcellular localization will help to understand the mechanism of action of “old” ER modulators and to design new ones with an optimized benefit/risk profile.

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“…ERα-46 lacks exon 1 encoding for the N-terminal TAD (AF-1), but it can dimerize with the wild-type ERα acting as a competitive inhibitor of ERα and suppressing breast cancer proliferation. ERα-46 is largely expressed in ERα-positive breast tumors, where the ERα-46/ERα-66 expression ratio inversely correlates with tumor size and grade [172]. The ∆3 and ∆7 isoforms, lacking exon 3 and 7, respectively, also act as DN splice variants, interfering with ERα-mediated transcriptional regulation.…”

Section: Estrogen Receptor Alpha (Erα)mentioning

confidence: 99%

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Belluti

Rigillo

Imbriano

2020

Cells

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Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

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The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

Cited by 55 publications

References 52 publications

Mechanisms for estrogen receptor expression in human cancer

Mechanisms for estrogen receptor expression in human cancer

Estrogen receptor subcellular localization and cardiometabolism

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

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