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VAV3 mediates resis...
VAV3 mediates resistance to breast cancer endocrine therapy
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- Aguilar, Helena (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Urruticoechea, Ander (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Halonen, Pasi (author)
- The Netherlands Cancer Institute, Amsterdam
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- Kiyotani, Kazuma (author)
- Center for Genomic Medicine, RIKEN, Yokohama, Japan
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- Mushiroda, Taisei (author)
- Center for Genomic Medicine, RIKEN, Yokohama, Japan
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- Barril, Xavier (author)
- University of Barcelona, Catalonia, Spain
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- Serra-Musach, Jordi (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Islam, Abul (author)
- University of Dhaka, Bangladesh
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- Caizzi, Livia (author)
- Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain
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- Di Croce, Luciano (author)
- Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain
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- Nevedomskaya, Ekaterina (author)
- The Netherlands Cancer Institute, Amsterdam
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- Zwart, Wilbert (author)
- The Netherlands Cancer Institute, Amsterdam
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- Bostner, Josefine (author)
- Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet
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- Karlsson, Elin (author)
- Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet
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- Perez-Tenorio, Gizeh (author)
- Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet
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- Fornander, Tommy (author)
- Karolinska Institutet
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- Sgroi, Dennis C (author)
- Massachusetts General Hospital, Boston, USA
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- Garcia-Mata, Rafael (author)
- University of North Carolina at Chapel Hill, USA
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- Jansen, Maurice Phm (author)
- Cancer Institute, Rotterdam, The Netherlands
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- García, Nadia (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Bonifaci, Núria (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Climent, Fina (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Soler, María Teresa (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Rodríguez-Vida, Alejo (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Gil, Miguel (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Brunet, Joan (author)
- Hospital Josep Trueta, Girona, Catalonia, Spain
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- Martrat, Griselda (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Gómez-Baldó, Laia (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Extremera, Ana I (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Figueras, Agnes (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Balart, Josep (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Clarke, Robert (author)
- Georgetown University Medical Center, Washington, DC, USA
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- Burnstein, Kerry L (author)
- University of Miami, Miller School of Medicine, Miami, FL, USA
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- Carlson, Kathryn E (author)
- University of Illinois, Urbana, USA
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- Katzenellenbogen, John A (author)
- University of Illinois, Urbana, USA
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- Vizoso, Miguel (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Esteller, Manel (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Villanueva, Alberto (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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- Rodríguez-Peña, Ana B (author)
- CSIC-University of Salamanca, Spain
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- Bustelo, Xosé R (author)
- CSIC-University of Salamanca, Spain
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- Nakamura, Yusuke (author)
- University of Tokyo, Japan
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- Zembutsu, Hitoshi (author)
- University of Tokyo, Japan
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- Stål, Olle (author)
- Östergötlands Läns Landsting,Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Onkologiska kliniken US
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- Beijersbergen, Roderick L (author)
- The Netherlands Cancer Institute, Amsterdam
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- Pujana, Miguel Angel (author)
- L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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(creator_code:org_t)
- 2014-05-28
- 2014
- English.
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In: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 16:3, s. R53-
- Related links:
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https://liu.diva-por... (primary) (Raw object)
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https://breast-cance...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Subject headings
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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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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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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show more...
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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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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
- Articles in the publication
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Breast Cancer Re ...
- By the university
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Linköping University
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Karolinska Institutet