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

  • Register
  • Log in
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • 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

Search

  • Advanced search
Cancer Research
Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
Endocrinology

Abstract 939: ErbB-2 inhibits Notch-4 expression and activity in breast cancer independent of ER function

Mingshan Lai, Kathleen Meeke and Clodia Osipo
Mingshan Lai
1Loyola Univ. Cardinal Bernardin Cancer Ctr., Maywood, IL
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kathleen Meeke
1Loyola Univ. Cardinal Bernardin Cancer Ctr., Maywood, IL
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clodia Osipo
1Loyola Univ. Cardinal Bernardin Cancer Ctr., Maywood, IL
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1538-7445.AM2012-939 Published April 2012
  • Article
  • Info & Metrics
Loading
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Abstract

Amplification, over-expression, and/or hyperactivity of ErbB-2 occur in 50% of breast tumors which include both luminal A/B and the HER2+ subtypes. Metastatic breast tumors that overexpress ErbB-2 are generally resistant to anti-hormonal or anti-HER2-targeted therapy. We have published that either 17beta-estradiol or overexpression of ErbB-2 suppresses Notch activity and this is reversed by inhibitors of estrogen receptor (ER) or ErbB-2. Furthermore, we demonstrated that when breast tumors are treated with a Notch inhibitor (gamma-secretase inhibitor or GSI) in combination with tamoxifen (ER+ cells) or trastuzumab (ErbB-2+ cells), ER+ breast tumor xenografts regress or ErbB-2+ xenografts do not recur. Based on these published findings, we asked in the current study by what mechanism does ErbB-2 inhibit Notch signaling. We used both genetic and pharmacologic approaches to address the hypothesis that ErbB-2 hyperactivity was sufficient to suppress Notch independent of ER function. Our results showed that Notch-4 transcription is specifically and significantly decreased when ErbB-2 or Heregulin-beta1 is stably-overexpressed in MCF-7 cells. Furthermore, the data demonstrated that while 17beta-estradiol inhibits Notch-4 mRNA and protein expression, which was reversed by fulvestrant, the inhibition on Notch-4 by ErbB-2 or by Heregulin-beta1 overexpression was independent of ER activity. In addition, we confirmed that ER status was an independent factor by specifically targeting ErbB-2 using lapatinib in ER negative SKBr3 breast cancer cells and the results showed that Notch-4 mRNA and protein increased to more than 100 fold compared to vehicle treatment. We have recently published that c-Fos is a potential transcriptional repressor of Notch-4 in breast cancer cells and in agreement, we identified that c-Fos levels were significantly elevated in breast cancer cells stably-overexpressing either ErbB-2 or Heregulin-beta1. The biological significance of Notch-4 overexpression was investigated in two relevant resistant models in vitro and in vivo. Resistance to lapatinib was prevented by co-treatment of a GSI plus lapatinib. Resistance to anti-hormonal therapy using long-term estrogen deprived MCF-7 cells was reversed by a GSI treatment. MCF-7/HER2 breast tumor xenografts regressed to undetectable levels with the combination of a GSI plus trastuzumab under conditoions where estrogen was deprived. In conclusion, results from the current study suggest that ErbB-2 overexpression or hyperactivity via Heregulin-beta1 is a potent inhibitor of Notch-4 expression possibly by increasing c-Fos expression. Furthermore, the regulation of Notch-4 expression is independent of ER function. More importantly, anti-ER or anti-EbB-2 targeted therapy de-repress Notch-4 expression and thus sensitize breast cancer cells to a Notch inhibitor such as a GSI to prevent or reverse resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 939. doi:1538-7445.AM2012-939

  • ©2012 American Association for Cancer Research
Back to top
Cancer Research: 72 (8 Supplement)
April 2012
Volume 72, Issue 8 Supplement
  • Table of Contents
  • Index by Author

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 939: ErbB-2 inhibits Notch-4 expression and activity in breast cancer independent of ER function
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
Citation Tools
Abstract 939: ErbB-2 inhibits Notch-4 expression and activity in breast cancer independent of ER function
Mingshan Lai, Kathleen Meeke and Clodia Osipo
Cancer Res April 15 2012 (72) (8 Supplement) 939; DOI: 10.1158/1538-7445.AM2012-939

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Abstract 939: ErbB-2 inhibits Notch-4 expression and activity in breast cancer independent of ER function
Mingshan Lai, Kathleen Meeke and Clodia Osipo
Cancer Res April 15 2012 (72) (8 Supplement) 939; DOI: 10.1158/1538-7445.AM2012-939
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

Endocrinology

  • Abstract LB-257: Estrogen signaling in mature luminal and luminal progenitor cells of BRCA2 carriers and non-carriers
  • Abstract LB-259: Pb203-AR-RMX conjugates for image-guided TAT of neuroendocrine tumors (NETs)
  • Abstract LB-258: Orphan nuclear hormone receptor, DAX-1, expression during progressive stages of invasive ductal carcimona
Show more 3

Poster Presentations - Proffered Abstracts

  • Abstract LB-236: Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013
  • Abstract LB-001: Impact of direct physician engagement with racial/ethnic minorities for oncology clinical trial access and accrual model
  • Abstract LB-107: EV-TRACK: transparent reporting and centralizing knowledge of extracellular vesicles to support the validation of extracellular vesicle biomarkers in cancer research
Show more 3

Poster Presentations - Steroid Hormone Receptor and Growth Factor Actions in Cancer 1

  • Abstract 949: Disruption of growth hormone signaling improves the efficacy of conventional chemotherapy in a rat model of mammary cancer
  • Abstract 946: Discovery of a novel benzotriazole-type retinoid X receptor partial-agonist decreasing plasma glucose level in type-2 diabetes mellitus with decreased side effects
  • Abstract 954: COX-2 inhibition reduces bone tumor growth in animal models:A role for celecoxib treatment in cAMP/protein kinase A-induced tumors
Show more 3
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

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

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Research

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

Copyright © 2018 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