VAV3 mediates resistance to breast cancer endocrine therapy

Helena Aguilar, Ander Urruticoechea, Pasi Halonen, Kazuma Kiyotani, Taisei Mushiroda, Xavier Barril, Jordi Serra-Musach, Abul Islam, Livia Caizzi, Luciano Di Croce, Ekaterina Nevedomskaya, Wilbert Zwart, Josefine Bostner, Elin Karlsson, Gizeh Pérez Tenorio, Tommy Fornander, Dennis C. Sgroi, Rafael Garcia-Mata, Maurice P H M Jansen, Nadia García & 25 others Núria Bonifaci, Fina Climent, María T. Soler, Alejo Rodríguez-Vida, Miguel Gil, Joan Brunet, Griselda Martrat, Laia Gómez-Baldó, Ana I. Extremera, Agnes Figueras, Josep Balart, Robert Clarke, Kerry L Burnstein, Kathryn E. Carlson, John A. Katzenellenbogen, Miguel Vizoso, Manel Esteller, Alberto Villanueva, Ana B. Rodríguez-Peña, Xosé R. Bustelo, Yusuke Nakamura, Hitoshi Zembutsu, Olle Stål, Roderick L. Beijersbergen, Miguel A. Pujana

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein 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 ERα 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 analysis 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 its association with therapeutic 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 was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα 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 the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 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 a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Original languageEnglish
Article numberR53
JournalBreast Cancer Research
Volume16
Issue number3
DOIs
StatePublished - May 28 2014

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Breast Neoplasms
Estrogen Receptors
Cell Survival
Therapeutics
Tamoxifen
Gene Expression
Small Interfering RNA
Molecular Docking Simulation
Neoplasms
Microarray Analysis
Tumor Biomarkers
Proteins
Biomarkers
Western Blotting
Alleles
Cell Proliferation
Cell Line
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Aguilar, H., Urruticoechea, A., Halonen, P., Kiyotani, K., Mushiroda, T., Barril, X., ... Pujana, M. A. (2014). VAV3 mediates resistance to breast cancer endocrine therapy. Breast Cancer Research, 16(3), [R53]. https://doi.org/10.1186/bcr3664

VAV3 mediates resistance to breast cancer endocrine therapy. / Aguilar, Helena; Urruticoechea, Ander; Halonen, Pasi; Kiyotani, Kazuma; Mushiroda, Taisei; Barril, Xavier; Serra-Musach, Jordi; Islam, Abul; Caizzi, Livia; Di Croce, Luciano; Nevedomskaya, Ekaterina; Zwart, Wilbert; Bostner, Josefine; Karlsson, Elin; Pérez Tenorio, Gizeh; Fornander, Tommy; Sgroi, Dennis C.; Garcia-Mata, Rafael; Jansen, Maurice P H M; García, Nadia; Bonifaci, Núria; Climent, Fina; Soler, María T.; Rodríguez-Vida, Alejo; Gil, Miguel; Brunet, Joan; Martrat, Griselda; Gómez-Baldó, Laia; Extremera, Ana I.; Figueras, Agnes; Balart, Josep; Clarke, Robert; Burnstein, Kerry L; Carlson, Kathryn E.; Katzenellenbogen, John A.; Vizoso, Miguel; Esteller, Manel; Villanueva, Alberto; Rodríguez-Peña, Ana B.; Bustelo, Xosé R.; Nakamura, Yusuke; Zembutsu, Hitoshi; Stål, Olle; Beijersbergen, Roderick L.; Pujana, Miguel A.

In: Breast Cancer Research, Vol. 16, No. 3, R53, 28.05.2014.

Research output: Contribution to journalArticle

Aguilar, H, Urruticoechea, A, Halonen, P, Kiyotani, K, Mushiroda, T, Barril, X, Serra-Musach, J, Islam, A, Caizzi, L, Di Croce, L, Nevedomskaya, E, Zwart, W, Bostner, J, Karlsson, E, Pérez Tenorio, G, Fornander, T, Sgroi, DC, Garcia-Mata, R, Jansen, MPHM, García, N, Bonifaci, N, Climent, F, Soler, MT, Rodríguez-Vida, A, Gil, M, Brunet, J, Martrat, G, Gómez-Baldó, L, Extremera, AI, Figueras, A, Balart, J, Clarke, R, Burnstein, KL, Carlson, KE, Katzenellenbogen, JA, Vizoso, M, Esteller, M, Villanueva, A, Rodríguez-Peña, AB, Bustelo, XR, Nakamura, Y, Zembutsu, H, Stål, O, Beijersbergen, RL & Pujana, MA 2014, 'VAV3 mediates resistance to breast cancer endocrine therapy', Breast Cancer Research, vol. 16, no. 3, R53. https://doi.org/10.1186/bcr3664
Aguilar H, Urruticoechea A, Halonen P, Kiyotani K, Mushiroda T, Barril X et al. VAV3 mediates resistance to breast cancer endocrine therapy. Breast Cancer Research. 2014 May 28;16(3). R53. https://doi.org/10.1186/bcr3664
Aguilar, Helena ; Urruticoechea, Ander ; Halonen, Pasi ; Kiyotani, Kazuma ; Mushiroda, Taisei ; Barril, Xavier ; Serra-Musach, Jordi ; Islam, Abul ; Caizzi, Livia ; Di Croce, Luciano ; Nevedomskaya, Ekaterina ; Zwart, Wilbert ; Bostner, Josefine ; Karlsson, Elin ; Pérez Tenorio, Gizeh ; Fornander, Tommy ; Sgroi, Dennis C. ; Garcia-Mata, Rafael ; Jansen, Maurice P H M ; García, Nadia ; Bonifaci, Núria ; Climent, Fina ; Soler, María T. ; Rodríguez-Vida, Alejo ; Gil, Miguel ; Brunet, Joan ; Martrat, Griselda ; Gómez-Baldó, Laia ; Extremera, Ana I. ; Figueras, Agnes ; Balart, Josep ; Clarke, Robert ; Burnstein, Kerry L ; Carlson, Kathryn E. ; Katzenellenbogen, John A. ; Vizoso, Miguel ; Esteller, Manel ; Villanueva, Alberto ; Rodríguez-Peña, Ana B. ; Bustelo, Xosé R. ; Nakamura, Yusuke ; Zembutsu, Hitoshi ; Stål, Olle ; Beijersbergen, Roderick L. ; Pujana, Miguel A. / VAV3 mediates resistance to breast cancer endocrine therapy. In: Breast Cancer Research. 2014 ; Vol. 16, No. 3.
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title = "VAV3 mediates resistance to breast cancer endocrine therapy",
abstract = "Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein 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 ERα 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 analysis 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 its association with therapeutic 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 was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα 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 the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 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 a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.",
author = "Helena Aguilar and Ander Urruticoechea and Pasi Halonen and Kazuma Kiyotani and Taisei Mushiroda and Xavier Barril and Jordi Serra-Musach and Abul Islam and Livia Caizzi and {Di Croce}, Luciano and Ekaterina Nevedomskaya and Wilbert Zwart and Josefine Bostner and Elin Karlsson and {P{\'e}rez Tenorio}, Gizeh and Tommy Fornander and Sgroi, {Dennis C.} and Rafael Garcia-Mata and Jansen, {Maurice P H M} and Nadia Garc{\'i}a and N{\'u}ria Bonifaci and Fina Climent and Soler, {Mar{\'i}a T.} and Alejo Rodr{\'i}guez-Vida and Miguel Gil and Joan Brunet and Griselda Martrat and Laia G{\'o}mez-Bald{\'o} and Extremera, {Ana I.} and Agnes Figueras and Josep Balart and Robert Clarke and Burnstein, {Kerry L} and Carlson, {Kathryn E.} and Katzenellenbogen, {John A.} and Miguel Vizoso and Manel Esteller and Alberto Villanueva and Rodr{\'i}guez-Pe{\~n}a, {Ana B.} and Bustelo, {Xos{\'e} R.} and Yusuke Nakamura and Hitoshi Zembutsu and Olle St{\aa}l and Beijersbergen, {Roderick L.} and Pujana, {Miguel A.}",
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TY - JOUR

T1 - VAV3 mediates resistance to breast cancer endocrine therapy

AU - Aguilar, Helena

AU - Urruticoechea, Ander

AU - Halonen, Pasi

AU - Kiyotani, Kazuma

AU - Mushiroda, Taisei

AU - Barril, Xavier

AU - Serra-Musach, Jordi

AU - Islam, Abul

AU - Caizzi, Livia

AU - Di Croce, Luciano

AU - Nevedomskaya, Ekaterina

AU - Zwart, Wilbert

AU - Bostner, Josefine

AU - Karlsson, Elin

AU - Pérez Tenorio, Gizeh

AU - Fornander, Tommy

AU - Sgroi, Dennis C.

AU - Garcia-Mata, Rafael

AU - Jansen, Maurice P H M

AU - García, Nadia

AU - Bonifaci, Núria

AU - Climent, Fina

AU - Soler, María T.

AU - Rodríguez-Vida, Alejo

AU - Gil, Miguel

AU - Brunet, Joan

AU - Martrat, Griselda

AU - Gómez-Baldó, Laia

AU - Extremera, Ana I.

AU - Figueras, Agnes

AU - Balart, Josep

AU - Clarke, Robert

AU - Burnstein, Kerry L

AU - Carlson, Kathryn E.

AU - Katzenellenbogen, John A.

AU - Vizoso, Miguel

AU - Esteller, Manel

AU - Villanueva, Alberto

AU - Rodríguez-Peña, Ana B.

AU - Bustelo, Xosé R.

AU - Nakamura, Yusuke

AU - Zembutsu, Hitoshi

AU - Stål, Olle

AU - Beijersbergen, Roderick L.

AU - Pujana, Miguel A.

PY - 2014/5/28

Y1 - 2014/5/28

N2 - Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein 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 ERα 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 analysis 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 its association with therapeutic 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 was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα 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 the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 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 a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

AB - Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein 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 ERα 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 analysis 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 its association with therapeutic 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 was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα 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 the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 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 a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

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