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VAV3 mediates resis...
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Aguilar, HelenaL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
VAV3 mediates resistance to breast cancer endocrine therapy
- Article/chapterEnglish2014
Publisher, publication year, extent ...
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2014-05-28
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BioMed Central,2014
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:liu-107051
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-107051URI
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https://doi.org/10.1186/bcr3664DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:130599615URI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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We wish to thank all study participants and their clinicians for their valuable contributions. This work was supported by grants from the Eugenio Rodriguez Pascual Foundation (2012, to MAP), the Government of Catalonia (2009-SGR283, to AV and MAP), the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01 DK015556, to JAK), the Red Cooperative Research Thematic Network on Cancer (RTICC) (12/0036/0002 to XRB and 12/0036/0008 to XRB and MAP) and the Spanish Ministry of Health, Fund for Health Research-Institute of Health Carlos III (11/00951 to AU and 12/01528 to MAP).
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INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Urruticoechea, AnderL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Halonen, PasiThe Netherlands Cancer Institute, Amsterdam
(author)
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Kiyotani, KazumaCenter for Genomic Medicine, RIKEN, Yokohama, Japan
(author)
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Mushiroda, TaiseiCenter for Genomic Medicine, RIKEN, Yokohama, Japan
(author)
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Barril, XavierUniversity of Barcelona, Catalonia, Spain
(author)
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Serra-Musach, JordiL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Islam, AbulUniversity of Dhaka, Bangladesh
(author)
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Caizzi, LiviaCentre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain
(author)
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Di Croce, LucianoCentre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain
(author)
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Nevedomskaya, EkaterinaThe Netherlands Cancer Institute, Amsterdam
(author)
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Zwart, WilbertThe Netherlands Cancer Institute, Amsterdam
(author)
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Bostner, JosefineLinköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet(Swepub:liu)josbo10
(author)
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Karlsson, ElinLinköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet(Swepub:liu)elika34
(author)
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Perez-Tenorio, GizehLinköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet(Swepub:liu)gizpe86
(author)
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Fornander, TommyKarolinska Institutet
(author)
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Sgroi, Dennis CMassachusetts General Hospital, Boston, USA
(author)
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Garcia-Mata, RafaelUniversity of North Carolina at Chapel Hill, USA
(author)
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Jansen, Maurice PhmCancer Institute, Rotterdam, The Netherlands
(author)
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García, NadiaL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Bonifaci, NúriaL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Climent, FinaL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Soler, María TeresaL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Rodríguez-Vida, AlejoL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Gil, MiguelL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Brunet, JoanHospital Josep Trueta, Girona, Catalonia, Spain
(author)
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Martrat, GriseldaL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Gómez-Baldó, LaiaL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Extremera, Ana IL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Figueras, AgnesL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Balart, JosepL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Clarke, RobertGeorgetown University Medical Center, Washington, DC, USA
(author)
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Burnstein, Kerry LUniversity of Miami, Miller School of Medicine, Miami, FL, USA
(author)
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Carlson, Kathryn EUniversity of Illinois, Urbana, USA
(author)
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Katzenellenbogen, John AUniversity of Illinois, Urbana, USA
(author)
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Vizoso, MiguelL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Esteller, ManelL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Villanueva, AlbertoL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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Rodríguez-Peña, Ana BCSIC-University of Salamanca, Spain
(author)
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Bustelo, Xosé RCSIC-University of Salamanca, Spain
(author)
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Nakamura, YusukeUniversity of Tokyo, Japan
(author)
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Zembutsu, HitoshiUniversity of Tokyo, Japan
(author)
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Stål, OlleÖstergötlands Läns Landsting,Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Onkologiska kliniken US(Swepub:liu)ollst87
(author)
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Beijersbergen, Roderick LThe Netherlands Cancer Institute, Amsterdam
(author)
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Pujana, Miguel AngelL’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
(author)
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L’Hospitalet del Llobregat, Barcelona, Catalonia, SpainThe Netherlands Cancer Institute, Amsterdam
(creator_code:org_t)
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In:Breast Cancer Research: BioMed Central16:3, s. R53-1465-54111465-542X
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Aguilar, Helena
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Urruticoechea, A ...
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Halonen, Pasi
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Kiyotani, Kazuma
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Mushiroda, Taise ...
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Barril, Xavier
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Serra-Musach, Jo ...
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Islam, Abul
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Caizzi, Livia
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Di Croce, Lucian ...
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Nevedomskaya, Ek ...
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Zwart, Wilbert
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Bostner, Josefin ...
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Karlsson, Elin
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Perez-Tenorio, G ...
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Fornander, Tommy
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Sgroi, Dennis C
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Garcia-Mata, Raf ...
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Jansen, Maurice ...
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García, Nadia
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Bonifaci, Núria
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Climent, Fina
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Soler, María Ter ...
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Rodríguez-Vida, ...
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Gil, Miguel
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Brunet, Joan
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Martrat, Griseld ...
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Gómez-Baldó, Lai ...
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Extremera, Ana I
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Figueras, Agnes
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Balart, Josep
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Clarke, Robert
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Burnstein, Kerry ...
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Carlson, Kathryn ...
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Katzenellenbogen ...
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Vizoso, Miguel
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Esteller, Manel
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Villanueva, Albe ...
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Rodríguez-Peña, ...
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Bustelo, Xosé R
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Nakamura, Yusuke
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Zembutsu, Hitosh ...
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Stål, Olle
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Beijersbergen, R ...
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Pujana, Miguel A ...
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Breast Cancer Re ...
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Linköping University
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Karolinska Institutet