Mechanisms of tamoxifen resistance

Ring, Alistair; Dowsett, Mitch

doi:10.1677/erc.1.00776

Cited by 552 publications

(483 citation statements)

References 90 publications

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“…Anti-ER therapy is one of the common used treatments in the cancer clinics. However, long-term anti-ER treatment results in drug resistance that may be likely due to activation EGFR signaling pathways (19)(20)(21). Thus, a strategy that dual blockade of EGFR and ER pathways is an important issue in antibreast cancer drug development.…”

Section: Discussionmentioning

confidence: 99%

“…For ERapositive breast cancer, anti-ER treatment strategies involve selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators, and disruption of estrogen synthesis (16)(17)(18). However, the long-term anti-ER treatment results in drug resistance due to activation of HER2/EGFR growth factor receptor pathway (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Taspine Derivative, HMQ1611, Inhibits Breast Cancer Cell Growth via Estrogen Receptor α and EGF Receptor Signaling Pathways

Zhan

Zhang

Liu

et al. 2012

Cancer Prevention Research

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Breast cancer is a common cancer with a leading cause of cancer mortality in women. Currently, the chemotherapy for breast cancer is underdeveloped. Here, we report a novel taspine derivative, HMQ1611, which has anticancer effects using in vitro and in vivo breast cancer models. HMQ1611 reduced cancer cell proliferation in four human breast cancer cell lines including MDA-MB-231, SK-BR-3, ZR-75-30, and MCF-7. HMQ1611 more potently reduced growth of estrogen receptor a (ERa)-positive breast cancer cells (ZR-75-30 and MCF-7) than ERa-negative cells (MDA-MB-231 and SK-BR-3). Moreover, HMQ1611 arrested breast cancer cell cycle at S-phase. In vivo tumor xenograft model, treatment of HMQ1611 significantly reduced tumor size and weight compared with vehicles. We also found that HMQ1611 reduced ERa expression and inhibited membrane ERa-mediated mitogenactivated protein kinase (MAPK) signaling following the stimulation of cells with estrogen. Knockdown of ERa by siRNA transfection in ZR-75-30 cells attenuated HMQ1611 effects. In contrast, overexpression of ERa in MDA-MB-231 cells enhanced HMQ1611 effects, suggesting that ERa pathway mediated HMQ1611 0 s inhibition of breast cancer cell growth in ERa-positive breast cancer. HMQ1611 also reduced phosphorylation of EGF receptor (EGFR) and its downstream signaling players extracellular signal-regulated kinase (ERK)1/2 and AKT activation both in ZR-75-30 and MDA-MB-231 cells. These results showed that the novel compound HMQ1611 had anticancer effects, and partially via ERa and/or EGFR signaling pathways, suggesting that HMQ1611 may be a potential novel candidate for human breast cancer intervention. Cancer Prev Res; 5(6); 864-73. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Taspine Derivative, HMQ1611, Inhibits Breast Cancer Cell Growth via Estrogen Receptor α and EGF Receptor Signaling Pathways

Zhan

Zhang

Liu

et al. 2012

Cancer Prevention Research

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“…Tamoxifen is the most widely used anti-oestrogen, with approximately 50% of women having ER-positive breast disease benefiting from this treatment [28,29]. However, acquisition of resistance to such therapies frequently arises and, in such cases, the identification of novel targets that promote a resistant phenotype may themselves prove useful targets through which the development of resistance and the associated tumour re-growth and spread may be delayed or prevented.…”

Section: Discussionmentioning

confidence: 99%

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

Hiscox

Jordan

Smith

et al. 2008

Breast Cancer Res Treat

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“…Since 1973, antiestrogen preparations of tamoxifen (TAM) have been widely used in endocrine therapy for breast cancer, and TAM is considered the standard treatment for estrogen receptor (ER)-positive patients until now. Unfortunately, approximately 40% of patients relapse after endocrine therapies [3]. Therefore, an essential understanding of the biological mechanism of antiestrogen resistance, especially the comprehension of TFs (transcription factors) regulation differences at transcriptional regulation level, will greatly promote the development of new drug targets discovery or novel treatment methods for breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation prediction of antiestrogen resistance in breast cancer based on RNA polymerase II binding data

Zhang

Wang

2014

BMC Bioinformatics

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BackgroundAlthough endocrine therapy impedes estrogen-ER signaling pathway and thus reduces breast cancer mortality, patients remain at continued risk of relapse after tamoxifen or other endocrine therapies. Understanding the mechanisms of endocrine resistance, particularly the role of transcriptional regulation is very important and necessary.MethodsWe propose a two-step workflow based on linear model to investigate the significant differences between MCF7 and OHT cells stimulated by 17β-estradiol (E2) respect to regulatory transcription factors (TFs) and their interactions. We additionally compared predicted regulatory TFs based on RNA polymerase II (PolII) binding quantity data and gene expression data, which were taken from MCF7/MCF7+E2 and OHT/OHT+E2 cell lines following the same analysis workflow. Enrichment analysis concerning diseases and cell functions and regulatory pattern analysis of different motifs of the same TF also were performed.ResultsThe results showed PolII data could provide more information and predict more recognizably important regulatory TFs. Large differences in TF regulatory mode were found between two cell lines. Through verified through GO annotation, enrichment analysis and related literature regarding these TFs, we found some regulatory TFs such as AP-1, C/EBP, FoxA1, GATA1, Oct-1 and NF-κB, maintained OHT cells through molecular interactions or signaling pathways that were different from the surviving MCF7 cells. From TF regulatory interaction network, we identified E2F, E2F-1 and AP-2 as hub-TFs in MCF7 cells; whereas, in addition to E2F and E2F-1, we identified C/EBP and Oct-1 as hub-TFs in OHT cells. Notably, we found the regulatory patterns of different motifs of the same TF were very different from one another sometimes.ConclusionsWe inferred some regulatory TFs, such as AP-1 and NF-κB, cooperated with ER through both genomic action and non-genomic action. The TFs that were involved in both protein-protein interactions and signaling pathways could be one of the key resistant mechanisms of endocrine therapy and thus also could be new treatment targets for endocrine resistance. Our flexible workflow could be integrated into an existing analytical framework and guide biologists to further determine underlying mechanisms in human diseases.

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Mechanisms of tamoxifen resistance

Cited by 552 publications

References 90 publications

A Novel Taspine Derivative, HMQ1611, Inhibits Breast Cancer Cell Growth via Estrogen Receptor α and EGF Receptor Signaling Pathways

A Novel Taspine Derivative, HMQ1611, Inhibits Breast Cancer Cell Growth via Estrogen Receptor α and EGF Receptor Signaling Pathways

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

Transcriptional regulation prediction of antiestrogen resistance in breast cancer based on RNA polymerase II binding data

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