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
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Computer Resources
      • Highly Cited Collection
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Early Career Award
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citations
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • 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 Research
Cancer Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Computer Resources
      • Highly Cited Collection
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Early Career Award
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citations
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Experimental and Molecular Therapeutics

Abstract 3812: Targeting BRCA1-deficient breast cancer by inhibition of the DEAD box RNA helicase DDX3X

Marise R. Heerma van Voss, Farhad Vesuna, Guus M. Bol, Paul J. van Diest and Venu Raman
Marise R. Heerma van Voss
1University Medical Center Utrecht, Utrecht, Netherlands;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Farhad Vesuna
2Johns Hopkins University, Baltimore, MD.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Guus M. Bol
1University Medical Center Utrecht, Utrecht, Netherlands;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul J. van Diest
1University Medical Center Utrecht, Utrecht, Netherlands;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Venu Raman
2Johns Hopkins University, Baltimore, MD.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1538-7445.AM2014-3812 Published October 2014
  • Article
  • Info & Metrics
Loading
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

Abstract

Introduction: The DEAD box RNA helicase DDX3X (DDX3) has been demonstrated to have a pro-oncogenic role in breast cancer. Thus, abrogating DDX3 activity was explored as a viable anti-cancer strategy using a small molecule inhibitor of DDX3, referred to as RK-33. RK-33 was found to inhibit non-homologous end joining (NHEJ), a DNA double strand break (DSB) repair mechanism. Therefore, we set out to determine the utility of RK-33 in breast cancers of BRCA1 mutation carriers, as they exhibit deficiencies in homologous recombination, an additional DSB repair mechanism. We hypothesized that BRCA1-deficient breast cancers would be more dependent on NHEJ to maintain genomic stability and thus inhibiting DDX3 activity by RK-33 would be an efficacious treatment strategy.

Methods: We evaluated DDX3 protein expression levels by immunohistochemistry in 102 BRCA1 and 29 BRCA2 germline mutation carriers and compared these to those of 345 sporadic breast cancer patients. In addition, DDX3 expression in two BRCA1-deficient (SUM149PT and HCC1937) and two BRCA1-proficient breast cancer cell lines (MCF-7 and MDA-MB-231) was quantified by immunoblotting. Furthermore, we compared the cell killing abilities of RK-33 in these BRCA1 pro- and deficient cell lines, as well as in MCF-7 cells before and after knockdown of BRCA1 by shRNA.

Results: High cytoplasmic DDX3 expression is less frequent in BRCA1 (24.5%) and BRCA2 (20.7%) related breast cancer, when compared to sporadic breast cancer (34.2%; OR 0.63; 95% CI 0.38-1.03; P = 0.065). This difference is statistically significant when correcting for higher grade and basal-like subtype in the group of BRCA1 mutation carriers (OR 0.33; 95% CI 0.14-0.77; P = 0.01). The BRCA1 pro- and deficient cell lines expressed similar levels of DDX3 and had a comparable sensitivity to RK-33 with IC-50 values ranging between 2 and 7 uM. Knockdown of BRCA1 in MCF-7 did not result in an increased sensitivity to RK-33.

Conclusion: DDX3 expression is lower in breast cancer in BRCA1 mutation carriers, when compared to sporadic breast cancers of similar grade and molecular subtype. BRCA1 pro- and deficient breast cancer cell lines are equally sensitive to inhibition of DDX3 by RK-33. This indicates that abrogating NHEJ activity by RK-33 results in cell death irrespective of additional deficiencies in the DNA repair pathway. Given that RK-33 showed good in vitro efficacy to kill all breast cancer cell lines, additional research is required to evaluate the use of RK-33 as a targeted chemotherapy agent for breast cancer.

Citation Format: Marise R. Heerma van Voss, Farhad Vesuna, Guus M. Bol, Paul J. van Diest, Venu Raman. Targeting BRCA1-deficient breast cancer by inhibition of the DEAD box RNA helicase DDX3X. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3812. doi:10.1158/1538-7445.AM2014-3812

  • ©2014 American Association for Cancer Research.
Previous
Back to top
Cancer Research: 74 (19 Supplement)
October 2014
Volume 74, Issue 19 Supplement
  • Table of Contents

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Research 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.
Abstract 3812: Targeting BRCA1-deficient breast cancer by inhibition of the DEAD box RNA helicase DDX3X
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Abstract 3812: Targeting BRCA1-deficient breast cancer by inhibition of the DEAD box RNA helicase DDX3X
Marise R. Heerma van Voss, Farhad Vesuna, Guus M. Bol, Paul J. van Diest and Venu Raman
Cancer Res October 1 2014 (74) (19 Supplement) 3812; DOI: 10.1158/1538-7445.AM2014-3812

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Abstract 3812: Targeting BRCA1-deficient breast cancer by inhibition of the DEAD box RNA helicase DDX3X
Marise R. Heerma van Voss, Farhad Vesuna, Guus M. Bol, Paul J. van Diest and Venu Raman
Cancer Res October 1 2014 (74) (19 Supplement) 3812; DOI: 10.1158/1538-7445.AM2014-3812
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
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

Experimental and Molecular Therapeutics

  • Abstract 6237: Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis
  • Abstract 2932: CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma
  • Abstract 6414: Using 3D models to test the efficacy of targeting cancer-associated fibroblast exosomes to overcome chemoresistance in pancreatic cancer
Show more Experimental and Molecular Therapeutics

Poster Presentations - Proffered Abstracts

  • Abstract PO-048: MicroRNA-10b is a regulator of cellular viability and proliferation in fibrolamellar carcinoma
  • Abstract PO-055: Pan-cancer metabolic profiling of the tumor microenvironment
  • Abstract PO-041: Genome-wide CRISPR/Cas9 screen reveals mitochondrial gene mutation as a driver for drug resistance in Ewing sarcoma
Show more Poster Presentations - Proffered Abstracts

Poster Presentations - Transcription Factors and Nuclear Targets

  • Abstract 3803: Obatoclax analogue SC-2001 inhibits STAT3 phosphorylation by enhancing protein tyrosine phosphatase SHP-1 expression and induces apoptosis in human breast cancer cells
  • Abstract 3808: Preclinical efficacy of the novel, oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) on castration resistant prostate cancer
  • Abstract 3807: A novel imidazole derivate inhibits STAT3 activation via induction of SHP-1 hepatocellular carcinoma
Show more Poster Presentations - Transcription Factors and Nuclear Targets
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

Advertisement