Lnc-DC promotes estrogen independent growth and tamoxifen resistance in 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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.9615 ◽

2011 ◽

Vol 29 (31) ◽

pp. 4160-4167 ◽

Cited By ~ 71

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.

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Estrogen Receptor-α Variant, ER-α36, is Involved in Tamoxifen Resistance and Estrogen Hypersensitivity

Endocrinology ◽

10.1210/en.2013-1116 ◽

2013 ◽

Vol 154 (6) ◽

pp. 1990-1998 ◽

Cited By ~ 33

Author(s):

XianTian Zhang ◽

Zhao-Yi Wang

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Molecular Mechanisms ◽

Underlying Mechanism ◽

Breast Cancer Patients ◽

High Concentration ◽

Mcf7 Cells ◽

Er Positive ◽

High Concentrations ◽

Positive Breast Cancer

Abstract Antiestrogens such as tamoxifen (TAM) provided a successful treatment for estrogen receptor (ER)-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to TAM therapy. The molecular mechanisms underlying TAM resistance have not been well established. Recently, we reported that breast cancer patients with tumors expressing high concentrations of ER-α36, a variant of ER-α, benefited less from TAM therapy than those with low concentrations of ER-α36, suggesting that increased ER-α36 concentration is one of the underlying mechanisms of TAM resistance. Here, we investigated the function and underlying mechanism of ER-α36 in TAM resistance. We found that TAM increased ER-α36 concentrations, and TAM-resistant MCF7 cells expressed high concentrations of ER-α36. In addition, MCF7 cells with forced expression of recombinant ER-α36 and H3396 cells expressing high concentrations of endogenous ER-α36 were resistant to TAM. ER-α36 down-regulation in TAM-resistant cells with the short hairpinRNA method restored TAM sensitivity. We also found that TAM acted as a potent agonist by activating phosphorylation of the AKT kinase in ER-α36-expressing cells. Finally, we found that cells with high concentration of ER-α36 protein were hypersensitive to estrogen, activating ERK phosphorylation at picomolar range. Our results thus demonstrated that elevated ER-α36 concentration is one of the mechanisms by which ER-positive breast cancer cells escape TAM therapy and provided a rational to develop novel therapeutic approaches for TAM-resistant patients by targeting ER-α36.

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

10.21203/rs.3.rs-39426/v1 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e11046 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e11046-e11046 ◽

Cited By ~ 3

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.

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Selective reduction of estrogen receptor (ER) positive breast cancer occurrence by estrogen receptor modulators supports etiological distinction between ER positive and ER negative breast cancers

Medical Hypotheses ◽

10.1016/j.mehy.2004.09.026 ◽

2005 ◽

Vol 64 (6) ◽

pp. 1182-1187 ◽

Cited By ~ 14

Author(s):

Sven Kurbel

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Selective Reduction ◽

Breast Cancers ◽

Estrogen Receptor Modulators ◽

Cancer Occurrence ◽

Er Positive ◽

Receptor Modulators ◽

Positive Breast Cancer

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Antitumor Activity and Underlying Mechanism of Phomoxanthone B in MCF7 Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620999201124215511 ◽

2020 ◽

Vol 20 ◽

Author(s):

Chuan Chen ◽

Ziyue Zhao ◽

Qian Dong ◽

XueHui Gao ◽

Huibin Xu ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Antitumor Activity ◽

Oxidative Phosphorylation ◽

Tumor Cells ◽

Transcriptome Analysis ◽

Mcf7 Cells ◽

Er Positive ◽

Induced Apoptosis ◽

Positive Breast Cancer

Background:: Xanthones are a class of heterocyclic natural products, which are promising sources of anticancer leads. Phomoxanthone B（PXB）and Phomoxanthone A（PXA）are xanthone dimers. PXA is well studied as an anti-cancer agent, but PXB is not. In our study, PXB was isolated from the endophytic fungus Phomopsis sp. By254. Objective:: The purpose of this study was to identify the underlying anti-tumor mechanisms of PXB in breast cancer MCF7 cell line. Methods:: Apoptosis, cell cycle, proliferation, invasion and migration assays were used to assess the antitumor activity of PXB. RNA sequencing was used to analyze the effect of PXB treatment on gene expression in MCF7 cells. Results:: PXB showed cytotoxicity toward a variety of tumor cells, especially MCF7 cells. PXB inhibited the migration and invasion, arrested cell cycle at G2/M phase and induced apoptosis associated with caspase-3 activation in MCF7 cells. The detailed transcriptome analysis revealed that PXB affected several pathways related to tumorigenesis, metabolisms-, and oxidative phosphorylation in MCF7 cells. KEGG transcriptome analysis revealed that PXB upregulated pro-survival signal pathways such as MAPK, PI3K-AKT and STAT3 pathways. We found that PXB also significantly upregulated the expression of IL24, DDIT3 and XAF1, which may contribute to PXB-induced apoptosis. We further found that PXB may downregulate oxidative phosphorylation by decreasing the expression of electron transport chain genes, especially MT-ND1, which is a potential unfavorable prognostic marker for ER-positive breast cancer. Conclusion:: PXB exerts strong cytotoxicity against human tumor cells and has a potential for ER-positive breast cancer treatment.

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.9616 ◽

2010 ◽

Vol 28 (7) ◽

pp. 1161-1167 ◽

Cited By ~ 75

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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