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VAV3 mediates resistance to breast cancer endocrine therapy

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

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