Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Reviewing
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Reviewing
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Research Articles

PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Yasir H. Ibrahim, Celina García-García, Violeta Serra, Lei He, Kristine Torres-Lockhart, Aleix Prat, Pilar Anton, Patricia Cozar, Marta Guzmán, Judit Grueso, Olga Rodríguez, Maria Teresa Calvo, Claudia Aura, Orland Díez, Isabel T. Rubio, José Pérez, Jordi Rodón, Javier Cortés, Leif W. Ellisen, Maurizio Scaltriti and José Baselga
Yasir H. Ibrahim
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Celina García-García
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Violeta Serra
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lei He
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kristine Torres-Lockhart
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Aleix Prat
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pilar Anton
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patricia Cozar
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marta Guzmán
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Judit Grueso
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Olga Rodríguez
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Teresa Calvo
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claudia Aura
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Orland Díez
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Isabel T. Rubio
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
José Pérez
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jordi Rodón
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Javier Cortés
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leif W. Ellisen
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maurizio Scaltriti
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
José Baselga
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
1Experimental Therapeutics Laboratory, 2Molecular Pathology, 3Breast Surgical Oncology, 4Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain; 5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; 6Massachusetts General Hospital Cancer Center, Massachusetts General Hospital; and 7Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/2159-8290.CD-11-0348 Published November 2012
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.

Significance: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs. Cancer Discov; 2(11); 1036–47. ©2012 AACR.

Read the Commentary on this article by Rehman et al., p. 982.

This article is highlighted in the In This Issue feature, p. 961

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received December 23, 2011.
  • Revision received July 23, 2012.
  • Accepted July 31, 2012.
  • ©2012 American Association for Cancer Research.

View Full Text
PreviousNext
Back to top
Cancer Discovery: 2 (11)
November 2012
Volume 2, Issue 11
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Discovery article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Yasir H. Ibrahim, Celina García-García, Violeta Serra, Lei He, Kristine Torres-Lockhart, Aleix Prat, Pilar Anton, Patricia Cozar, Marta Guzmán, Judit Grueso, Olga Rodríguez, Maria Teresa Calvo, Claudia Aura, Orland Díez, Isabel T. Rubio, José Pérez, Jordi Rodón, Javier Cortés, Leif W. Ellisen, Maurizio Scaltriti and José Baselga
Cancer Discov November 1 2012 (2) (11) 1036-1047; DOI: 10.1158/2159-8290.CD-11-0348

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Yasir H. Ibrahim, Celina García-García, Violeta Serra, Lei He, Kristine Torres-Lockhart, Aleix Prat, Pilar Anton, Patricia Cozar, Marta Guzmán, Judit Grueso, Olga Rodríguez, Maria Teresa Calvo, Claudia Aura, Orland Díez, Isabel T. Rubio, José Pérez, Jordi Rodón, Javier Cortés, Leif W. Ellisen, Maurizio Scaltriti and José Baselga
Cancer Discov November 1 2012 (2) (11) 1036-1047; DOI: 10.1158/2159-8290.CD-11-0348
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Results
    • Discussion
    • Methods
    • Disclosure of Potential Conflicts of Interest
    • Authors' Contributions
    • Grant Support
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Correction of FPR1 Defect
  • Somatic Mutations and Cancer Risk in Skin across the Body
  • xDFG Mutations Confer Type II TRK TKI Sensitivity
Show more Research Articles
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement