scholarly journals Tripartite motif-containing 3 (TRIM3) enhances ER signaling and confers tamoxifen resistance in breast cancer

Oncogenesis ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Runyi Ye ◽  
NiJiati AiErken ◽  
Xiaying Kuang ◽  
Huijuan Zeng ◽  
Nan Shao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Tamoxifen Resistance ◽  
Clinical Problem ◽  
E3 Ligases ◽  
New Class ◽  
Tripartite Motif ◽  
Er Positive ◽  
And Function ◽  
Trim Proteins

AbstractTamoxifen resistance remains a clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. Tripartite motif-containing (TRIM) proteins are a new class of SUMO E3 ligases, which regulate the SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and the response to tamoxifen remain unclear. In the present study, we observed that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance. Furthermore, TRIM3 overexpression significantly correlated with poor survival of patients with ER+ breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking down of TRIM3 reduced these capabilities. Moreover, TRIM3, as a ubiquitin carrier protein 9 (UBC9) binding protein, promoted SUMO modification of estrogen receptor 1 (ESR1) and activated the ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance. These results suggest TRIM3 as a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen might provide a potential treatment for breast cancer.

scholarly journals Tripartite Motif-Containing 3 (TRIM3) Enhances ER Signaling and Confers Tamoxifen Resistance in Breast Cancer

2020 ◽  
Author(s):  
Run-yi Ye ◽  
Xia-ying Kuang ◽  
Hui-juan Zeng ◽  
Nan Shao ◽  
ying lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanism ◽  
Western Blotting ◽  
Tamoxifen Resistance ◽  
Clinical Problem ◽  
Breast Cancer Cell Lines ◽  
E3 Ligases ◽  
And Function

Abstract Background: Tamoxifen resistance remains a tricky clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. TRIM proteins are a new class of SUMO E3 ligases, regulating SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and response to tamoxifen remains unclear.Methods: The expression of TRIM3 was assessed in 48 cases with breast cancer which received tamoxifen therapy. The protein and RNA levels of TRIM3 in 12 ER+ breast cancer cell lines were assessed by Western blotting and qRT-PCR assays. Effects of TRIM3 in regulating tamoxifen resistance were evaluated both in vitro and in vivo via Cell viability, Colony formation, Anchorage-independent growth ability assays and Tumor xenografts. Molecular mechanism of TRIM3 in regulating SUMOylation of ERα was analyzed by Western blotting, Immunoprecipitation, Far Western blotting and Luciferase activity assays.Results: We reported that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance., Furthermore,TRIM3 overexpression significantly correlated with poor survival of ER+ breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking downTRIM3 reduced these capabilities. Moreover, TRIM3, as a UBC9 binding protein, promoted SUMO modification of ESR1 and activated ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance.Conclusions: These results suggest a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen may provide a potential treatment for breast cancer.

A study on platinum(iv) species containing an estrogen receptor modulator to reverse tamoxifen resistance of breast cancer

Metallomics ◽  
2018 ◽  
Vol 10 (2) ◽  
pp. 346-359 ◽  
Author(s):  
Weiwei Hu ◽  
Jian Zhao ◽  
Wuyang Hua ◽  
Shaohua Gou
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cell Line ◽  
Tamoxifen Resistance ◽  
Receptor Modulator ◽  
Er Positive ◽  
Dual Action ◽  
Line P ◽  
Mcf 7

Dual-action Tam–Pt(iv) complexes increase the accumulation of platinum in ER-positive cancer cells and reverse the resistance of the TamR-MCF-7 cell line.

scholarly journals Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

2011 ◽  
Vol 29 (31) ◽  
pp. 4160-4167 ◽  
Author(s):  
Chungyeul Kim ◽  
Gong Tang ◽  
Katherine L. Pogue-Geile ◽  
Joseph P. Costantino ◽  
Frederick L. Baehner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Tamoxifen Resistance ◽  
Linear Predictor ◽  
Treatment And Prevention ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

scholarly journals Network-based Approach to Identify Prognosis-related Genes in Tamoxifen-treated Patients With Estrogen Receptor-positive Breast Cancer

2020 ◽  
Author(s):  
Yanyan Wang ◽  
Xiaonan Gong ◽  
Yujie Zhang
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Targeting ◽  
Quantitative Polymerase Chain Reaction ◽  
Tamoxifen Resistance ◽  
The Cancer Genome Atlas ◽  
Tamoxifen Treatment ◽  
Hub Genes ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Background: The estrogen receptor (ER) antagonist tamoxifen is the most commonly used endocrine therapy for ER-positive breast cancer. However, tamoxifen resistance remains a major cause of cancer recurrence and progression. Here, we aimed to identify hub genes involved in the progression and prognosis of ER-positive breast cancer following tamoxifen treatment.Results: Microarray data (GSE9838) for 155 tamoxifen-treated primary ER-positive breast cancer samples were obtained from the Gene Expression Omnibus database. In total, 1706 differentially expressed genes (DEGs) associated with tamoxifen resistance, including 859 upregulated genes and 847 downregulated genes, were identified. These DEGs were mainly enriched in functions such as protein targeting to the ER and pathways such as ribosome and oxidative phosphorylation.Weighted correlation network analysis (WGCNA) clustered genes into 13 modules, among which the tan and blue modules were the most significantly related to prognosis. From these two modules, we further identified three prognosis-related hub genes (GRSF1, MAPT, and REC8) via survival analysis. High expression ofGRSF1 predicted poor prognosis, whereas MAPT andREC8indicated favorable survival outcomes in all patients with breast cancer and in patients with ER-positive breast cancer based on The Cancer Genome Atlas database. These hub genes were further verified by reverse transcription quantitative polymerase chain reaction.Conclusion: Our findings established novel prognostic biomarkers to predict tamoxifen sensitivity, which may facilitate individualized management of breast cancer.

scholarly journals Pushing estrogen receptor around in breast cancer

2016 ◽  
Vol 23 (12) ◽  
pp. T227-T241 ◽  
Author(s):  
Elgene Lim ◽  
Gerard Tarulli ◽  
Neil Portman ◽  
Theresa E Hickey ◽  
Wayne D Tilley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Clinical Problem ◽  
Estrogen Receptor Α ◽  
Normal Breast ◽  
Favourable Outcome ◽  
Breast Cancers ◽  
Er Positive ◽  
Tumorigenic Activity ◽  
Positive Breast Cancer

The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to ‘push’ ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.

Overexpression of Notch-1 induced tamoxifen resistance through down regulation of ESR1 in positive estrogen receptor breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11046-e11046 ◽  
Author(s):  
Nasser Ghaly Yousif ◽  
Majid Al-Matwari
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Acquired Resistance ◽  
Prognostic Significance ◽  
Tamoxifen Resistance ◽  
Notch Signaling Pathway ◽  
Notch 1 ◽  
Estrogen Receptor Positive ◽  
Er Positive ◽  
Positive Breast Cancer

e11046 Background: Tamoxifen is one of the most widely used drugs in the treatment of estrogen-receptor positive breast cancer, and acquired resistance to tamoxifen during treatment are largely unknown and recent research showed that lower levels of ESR1 associated with tamoxifen resistance in ER-positive breast tumors, from other hand highly expression of Notch-1 and/or Jagged-1 has negative prognostic significance in breast cancer, in this study we show the cross-talk between Notch and the lower levels of ESR1 estrogen receptor positive breast cancer. Methods: A retrospective study with clinico-pathological analysis of 195 patients had ER-positive breast cancer used tamoxifen as an adjuvant systemic therapy, gene expression profiling of paraffin-embedded tumors for ESR1, Real-time PCR and Western blot analysis were performed to detect Notch-1/Jagged-1. Results: From 195 patients 32% had tamoxifen resistance which related with lower levels of ESR1 expression (P=0.019) and there was, a highly significant association of over expression Notch1 protein with the lower levels of ESR1 (P=0.006). Conclusions: The results from this study demonstrate for the first time that Notch-1 regulate levels of ESR1 in ER-positive breast cancer, and partly responsible for tamoxifen resistance, the Notch signaling pathway may be a potential therapeutic target beside current breast cancer therapy and need further investigation to know the mechanism of this pathway.

scholarly journals Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Wan-Xin Peng ◽  
Pratirodh Koirala ◽  
Huaixiang Zhou ◽  
Jiahong Jiang ◽  
Ziqiang Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Treated Patient ◽  
Tamoxifen Resistance ◽  
Underlying Mechanism ◽  
Autocrine Loop ◽  
Estrogen Receptor Modulators ◽  
Er Positive ◽  
Induced Apoptosis ◽  
Positive Breast Cancer

AbstractSelective estrogen receptor modulators (SERMs) such as tamoxifen have proven to be effective in the treatment of estrogen receptor (ER) positive breast cancer. However, a major obstacle for such endocrine therapy is estrogen independent growth, leading to resistance, and the underlying mechanism is not fully understood. The purpose of this study was to determine whether long non-coding RNAs (lncRNAs) are involved in regulation of estrogen independent growth and tamoxifen resistance in ER positive breast cancer. Using a CRISPR/Cas9-based SAM (synergistic activation mediator) library against a focus group of lncRNAs, we identify Lnc-DC as a candidate lncRNA. Further analysis suggests that Lnc-DC is able to reduce tamoxifen-induced apoptosis by upregulation of anti-apoptotic genes such as Bcl2 and Bcl-xL. Furthermore, Lnc-DC activates STAT3 by phosphorylation (pSTAT3Y705), and the activated STAT3 subsequently induces expression of cytokines which in turn activate STAT3, forming an autocrine loop. Clinically, upregulation of Lnc-DC is associated with poor prognosis. In particular, analysis of a tamoxifen-treated patient cohort indicates that Lnc-DC expression can predict the response to tamoxifen. Together, this study demonstrates a previously uncharacterized function of Lnc-DC/STAT3/cytokine axis in estrogen independent growth and tamoxifen resistance, and Lnc-DC may serve as a potential predictor for tamoxifen response.

scholarly journals G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer

2011 ◽  
Vol 128 (2) ◽  
pp. 457-466 ◽  
Author(s):  
Atanas Ignatov ◽  
Tanja Ignatov ◽  
Christine Weißenborn ◽  
Holm Eggemann ◽  
Joachim Bischoff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
G Protein ◽  
Tamoxifen Resistance ◽  
G Protein Coupled

scholarly journals Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

2010 ◽  
Vol 28 (7) ◽  
pp. 1161-1167 ◽  
Author(s):  
Anita K. Dunbier ◽  
Helen Anderson ◽  
Zara Ghazoui ◽  
Elizabeth J. Folkerd ◽  
Roger A'Hern ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Multivariable Analysis ◽  
Independent Set ◽  
Breast Cancers ◽  
Plasma Estradiol ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women. Materials and Methods Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively). Conclusion Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

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