Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells

Aby Joiakim, Patricia A. Mathieu, Catherine Shelp, Julie Boerner and John J. Reiners Jr.
Drug Metabolism and Disposition May 2016, 44 (5) 665-671; DOI: https://doi.org/10.1124/dmd.115.066274
Aby Joiakim
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan (A.J., P.A.M., J.J.R.); Department of Pharmacology (C.S., J.J.R.) and Department of Oncology (J.B.), Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patricia A. Mathieu
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan (A.J., P.A.M., J.J.R.); Department of Pharmacology (C.S., J.J.R.) and Department of Oncology (J.B.), Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Catherine Shelp
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan (A.J., P.A.M., J.J.R.); Department of Pharmacology (C.S., J.J.R.) and Department of Oncology (J.B.), Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julie Boerner
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan (A.J., P.A.M., J.J.R.); Department of Pharmacology (C.S., J.J.R.) and Department of Oncology (J.B.), Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John J. Reiners Jr.
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan (A.J., P.A.M., J.J.R.); Department of Pharmacology (C.S., J.J.R.) and Department of Oncology (J.B.), Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

CYP1A1 and CYP1A2 are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e., phosphorylated) forms of extracellular regulated kinases (ERKs) and the epidermal growth factor receptor (EGFR). Shifting to serum/EGF-deficient medium also enhanced TCDD-mediated induction of cytochrome P450 (CYP)1A1. Treatment of cells cultured in complete medium with the EGFR inhibitors gefitinib (Iressa), AG1478, and CI-1033 resulted in concentration-dependent reductions of active EGFR and ERKs, and increased CYP1A1 mRNA content ∼3- to 18-fold above basal level. EGFR inhibitors synergized with TCDD and resulted in transient CYP1A1 and CYP1A2 mRNA accumulations ∼8-fold greater (maximum at 5 hours) than that achieved with only TCDD. AG1478, gefitinib, and TCDD individually induced small increases (∼1.2- to 2.5-fold) in CYP1A1 protein content but did not cause additive or synergistic accumulations of CYP1A1 protein when used in combination. The mitogen-activated protein kinase kinase inhibitor PD184352 inhibited ERK and EGFR activation in a concentration-dependent fashion without causing CYP1A1 mRNA accumulation. However, cotreatment with PD184352 potentiated TCDD-mediated CYP1A1 induction. TCDD-mediated induction of CYP1A1 in MCF7-TETon-EGFR cells, a MCF7 variant in which EGFR expression can be controlled, was not affected by the activity status of EGFR or ERKs. Hence, EGFR signaling mutes both basal and ligand-induced expression of two aryl hydrocarbon receptor–responsive P450s in MCF10A cultures. However, these effects are cell context–dependent. Furthermore, CYP1A1 mRNA and protein abundance are not closely coupled in MCF10A cultures.

Footnotes

    • Received July 10, 2015.
    • Accepted March 3, 2016.
  • ↵1 Current affiliation: Detroit R & D, Inc., 2727 Second Ave., Suite 4113, Detroit, MI, 48201.

  • ↵2 Current affiliation: BASF Corporation, 24710 West 11 Mile Rd., Southfield, MI 48033.

  • A portion of this work was supported by Congressionally Directed Medical Research Programs [Grant W81XWH-13-1-0097].

  • dx.doi.org/10.1124/dmd.115.066274.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 44 (5)
Drug Metabolism and Disposition
Vol. 44, Issue 5
1 May 2016
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition 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.
Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

EGFR Signaling Regulates AhR Function

Aby Joiakim, Patricia A. Mathieu, Catherine Shelp, Julie Boerner and John J. Reiners
Drug Metabolism and Disposition May 1, 2016, 44 (5) 665-671; DOI: https://doi.org/10.1124/dmd.115.066274

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

EGFR Signaling Regulates AhR Function

Aby Joiakim, Patricia A. Mathieu, Catherine Shelp, Julie Boerner and John J. Reiners
Drug Metabolism and Disposition May 1, 2016, 44 (5) 665-671; DOI: https://doi.org/10.1124/dmd.115.066274
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Human ADME Properties of Abrocitinib
  • MSCs Pharmacokinetics under liver diseases
  • In Vitro P450 Suppression by Peptide Not Observed in Clinic
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2022 by the American Society for Pharmacology and Experimental Therapeutics