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Loss of TGF beta Re...
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Busch, SusannGothenburg University, Sweden
(författare)
Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
- Artikel/kapitelEngelska2015
Förlag, utgivningsår, omfång ...
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American Association for Cancer Research,2015
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:liu-117366
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-117366URI
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https://doi.org/10.1158/0008-5472.CAN-14-1583DOI
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https://lup.lub.lu.se/record/5277774URI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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Funding Agencies|Swedish Cancer Society; Breakthrough Breast Cancer UK; BioCARE-a National Strategic Research Program at University of Gothenburg
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One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Sims, Andrew H.University of Edinburgh, Scotland
(författare)
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Stål, OlleLinköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Region Östergötland, Onkologiska kliniken US(Swepub:liu)ollst87
(författare)
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Fernö, MårtenLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University, Sweden(Swepub:lu)onk-mfe
(författare)
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Landberg, GoranGothenburg University, Sweden; University of Manchester, England
(författare)
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Gothenburg University, SwedenUniversity of Edinburgh, Scotland
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Cancer Research: American Association for Cancer Research75:7, s. 1457-14690008-54721538-7445
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