Abstract:
:Resistance to tamoxifen is a major clinical challenge in the treatment of breast cancer; however, it is still unclear which signaling pathways are the major drivers of tamoxifen-resistant growth. To characterize resistance mechanisms, we have generated different tamoxifen-resistant breast cancer cell lines from MCF-7. In this model, we investigated whether signaling from human epidermal growth factor receptors (HERs), their downstream kinases, or from the estrogen receptor α (ERα) was driving tamoxifen-resistant cell growth. Increased expression of EGFR and increased phosphorylation of HER3 were observed upon acquisition of tamoxifen resistance, and the extracellular activated kinase (ERK) signaling pathway was highly activated in the resistant cells. The EGFR inhibitor gefitinib and the ERK pathway inhibitor U0126 resulted in partial and preferential growth inhibition of tamoxifen-resistant cells. All the tamoxifen-resistant cell lines retained ERα expression but at a lower level compared to that in MCF-7. Importantly, we showed via ERα knockdown that the tamoxifen-resistant cells were dependent on functional ERα for growth and we observed a clear growth stimulation of resistant cell lines with clinically relevant concentrations of tamoxifen and 4-OH-tamoxifen, indicating that tamoxifen-resistant cells utilize agonistic ERα stimulation by tamoxifen for growth. The tamoxifen-resistant cells displayed high phosphorylation of ERα at Ser118 in the presence of tamoxifen; however, treatment with U0126 neither affected the level of Ser118 phosphorylation nor expression of the ERα target Bcl-2, suggesting that ERK contributes to cell growth independently of ERα in our cell model. In support of this, combined treatment against ERα and ERK signaling in resistant cells was superior to single-agent treatment and as effective as fulvestrant treatment of MCF-7 cells. Together, these findings demonstrate that ERα is a major driver of growth in tamoxifen-resistant cells supported by HER/ERK growth signaling, implying that combined targeting of these pathways may have a clinical potential for overcoming tamoxifen resistance.
journal_name
Breast Cancer Res Treatjournal_title
Breast cancer research and treatmentauthors
Thrane S,Lykkesfeldt AE,Larsen MS,Sorensen BS,Yde CWdoi
10.1007/s10549-013-2485-2subject
Has Abstractpub_date
2013-05-01 00:00:00pages
71-80issue
1eissn
0167-6806issn
1573-7217journal_volume
139pub_type
杂志文章abstract::We evaluated the question of whether the chemosensitizers verapamil and quinine given orally to breast cancer patients failing combination chemotherapy alone would result in additional clinical responses. In vitro studies reported here showed verapamil sensitization of Adriamycin resistance in 18.8% of fresh human bre...
journal_title:Breast cancer research and treatment
pub_type: 临床试验,杂志文章
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/BF01833517
更新日期:1992-01-01 00:00:00
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章,评审
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journal_title:Breast cancer research and treatment
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1007/BF01807140
更新日期:1990-08-01 00:00:00
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s10549-010-0927-7
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
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doi:10.1007/s10549-007-9769-3
更新日期:2008-09-01 00:00:00
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journal_title:Breast cancer research and treatment
pub_type: 临床试验,杂志文章,多中心研究
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章,meta分析
doi:10.1007/s10549-010-0872-5
更新日期:2010-11-01 00:00:00
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-016-3835-7
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1023/B:BREA.0000041622.30169.16
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-012-2035-3
更新日期:2012-07-01 00:00:00
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-015-3427-y
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章,meta分析
doi:10.1007/s10549-019-05477-5
更新日期:2020-01-01 00:00:00
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-005-9083-x
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doi:10.1007/s10549-009-0619-3
更新日期:2010-08-01 00:00:00