REGγ regulates ERα degradation via ubiquitin–proteasome pathway in breast cancer

Chai, Fang; Liang, Yan; Bi, Jiong; Chen, Li; Zhang, Fan; Cui, You‐Hong; Jiang, Jun

doi:10.1016/j.bbrc.2014.11.124

Cited by 21 publications

(13 citation statements)

References 29 publications

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“…In contrast to observations in T47D cells, we found that while ZnT2 mRNA expression in MDA-MB-231 cells was similar to that in MCF10A cells, there was significantly less ZnT2 protein in MDA-MB-231 cells. Similar to estrogen receptor alpha [ 54 ], we found that ZnT2 was robustly degraded in the proteome, perhaps as a feature of enhanced proteasomal degradation machinery [ 55 ]. However, another postulate is that ZnT2 may also be post-transcriptionally regulated by microRNAs.…”

Section: Discussionmentioning

confidence: 99%

Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer

et al. 2016

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BackgroundZinc (Zn) hyper-accumulates in breast tumors and malignant cell lines compared to normal mammary epithelium. The mechanisms responsible for Zn accumulation and the consequence of Zn dysregulation are poorly understood.MethodsMicroarrays were performed to assess differences in the expression of Zn transporters and metallothioneins (MTs) in human breast tumors and breast cancer cell lines. Real-time PCR and immunoblotting were employed to profile Zn transporter expression in representative luminal (T47D), basal (MDA-MB-231), and non-malignant (MCF10A) cell lines. Zn distribution in human tumors was assessed by X-ray fluorescence imaging. Zn distribution and content in cell lines was measured using FluoZin-3 imaging, and quantification and atomic absorption spectroscopy. Functional consequences of ZnT2 over-expression in MDA-MB-231 cells including invasion, proliferation, and cell cycle were measured using Boyden chambers, MTT assays, and flow cytometry, respectively.ResultsGene expression profiling of human breast tumors and breast cancer cell lines identified subtype-specific dysregulation in the Zn transporting network. X-ray fluorescence imaging of breast tumor tissues revealed Zn hyper-accumulation at the margins of Luminal breast tumors while Zn was more evenly distributed within Basal tumors. While both T47D and MDA-MB-231 cells hyper-accumulated Zn relative to MCF10A cells, T47D cells accumulated 2.5-fold more Zn compared to MDA-MB-231 cells. FluoZin-3 imaging indicated that Zn was sequestered into numerous large vesicles in T47D cells, but was retained in the cytoplasm and found in fewer and larger, amorphous sub-cellular compartments in MDA-MB-231 cells. The differences in Zn localization mirrored the relative abundance of the Zn transporter ZnT2; T47D cells over-expressed ZnT2, whereas MDA-MB-231 cells did not express ZnT2 protein due to proteasomal degradation. To determine the functional relevance of the lack of ZnT2 in MDA-MB-231cells, cells were transfected to express ZnT2. ZnT2 over-expression led to Zn vesicularization, shifts in cell cycle, enhanced apoptosis, and reduced proliferation and invasion.ConclusionsThis comprehensive analysis of the Zn transporting network in malignant breast tumors and cell lines illustrates that distinct subtype-specific dysregulation of Zn management may underlie phenotypic characteristics of breast cancers such as grade, invasiveness, metastatic potential, and response to therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0486-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer

et al. 2016

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“…The close relationship between ERα and proteasomes in malignant tumor cells was also confirmed by Thaler S. et al, who showed that bortezomib inhibited ERα expression and induced the death of ERα + breast cancer cells [120]. A study of breast cancer tissue revealed the positive correlation between the expression of proteasome activator REGγ and ERα status [121]. On the whole, the development of estrogen-dependent malignant tumors is accompanied by an increase in the chymotrypsin-like activity of the proteasomes and a change in their subunit composition [122][123][124].…”

Section: Mutual Regulation Of Estrogen Receptors and Ubiquitin Proteamentioning

confidence: 59%

Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation

et al. 2020

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This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of proteasomes and mechanisms of protein ubiquitination and cleavage are described. According to the modern concept, the ubiquitin proteasome system (UPS) is involved in the regulation of the activity of ERs in several ways. First, UPS performs the ubiquitination of ERs with a change in their functional activity. Second, UPS degrades ERs and their transcriptional regulators. Third, UPS affects the expression of ER genes. In addition, the opportunity of the regulation of proteasome functioning by ERs—in particular, the expression of immune proteasomes—is discussed. Understanding the complex mechanisms underlying the regulation of ERs and proteasomes has great prospects for the development of new therapeutic agents that can make a significant contribution to the treatment of diseases associated with the impaired function of these biomolecules.

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“…For instance, it has been suggested that Src-dependent phosphorylation of ERα allows E6AP to polyubiquitinate and induce the degradation of this receptor. However, PEBP4 (phosphatidyl ethanolamine-binding protein 4) protein[ 69 , 70 ] interacts with Src, blocking the phosphorylation and degradation of ERα induced by Src[ 69 ].…”

Section: Is Erα In Breast Cancer Cells Polyubiquitinated and Degradedmentioning

confidence: 99%

“…Furthermore, although the mechanisms are unclear, it has been reported that ERα protein levels decrease in cells with low levels of REGγ (PA28γ, a nuclear proteasome coactivator), but when the proteasome is inhibited by MG132 treatment, ERα protein levels are recovered, suggesting that downregulation of REGγ promotes ERα polyubiquitination and degradation. High levels of REGγ and ERα in breast tumors correlated with poor prognosis in patients with breast cancer[ 69 ].…”

Section: Is Erα In Breast Cancer Cells Polyubiquitinated and Degradedmentioning

confidence: 99%

Polyubiquitination inhibition of estrogen receptor alpha and its implications in breast cancer

Tecalco-Cruz

Ramírez-Jarquín

2018

WJCO

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Estrogen receptor alpha (ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear activity of ERα is related to endocrine therapy resistance. ERα polyubiquitination is induced by the estradiol hormone, and also by selective estrogen receptor degraders, resulting in ERα degradation via the ubiquitin proteasome system. Moreover, polyubiquitination is related to the ERα transcription cycle, and some E3-ubiquitin ligases also function as coactivators for ERα. Several studies have demonstrated that ERα polyubiquitination is inhibited by multiple mechanisms that include posttranslational modifications, interactions with coregulators, and formation of specific protein complexes with ERα. These events are responsible for an increase in ERα protein levels and deregulation of its signaling in breast cancers. Thus, ERα polyubiquitination inhibition may be a key factor in the progression of breast cancer and resistance to endocrine therapy.

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REGγ regulates ERα degradation via ubiquitin–proteasome pathway in breast cancer

Cited by 21 publications

References 29 publications

Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer

Subtype-specific accumulation of intracellular zinc pools is associated with the malignant phenotype in breast cancer

Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation

Polyubiquitination inhibition of estrogen receptor alpha and its implications in breast cancer

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