Acetaminophen-induced proliferation of estrogen-responsive breast cancer cells is associated with increases in c-myc RNA expression and NF-κB activity

Samantha L. Gadd, Gerry Hobbs, Michael R. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Studies reported here tested the hypothesis that acetaminophen stimulates proliferation of E2-responsive cells by inducing expression of E2-regulated genes. Ribonuclease protection assays compared the effects of acetaminophen and E2 on expression of selected genes (c-myc, c-fos, cyclin D1, bcl-2, bax, gadd45, mcl-1, p53, p21CIP1/WAF1, and bcl-xL) in E2-responsive breast cancer (MCF-7) and endometrial adenocarcinoma (Ishikawa) cells as well as in E2-nonresponsive (MDA-MB-231) breast cancer cells. Acetaminophen and E2 increased c-myc RNA levels in MCF-7 cells, consistent with a mitogenic activity of these compounds in MCF-7 cells. However, the magnitude and time course of acetaminophen and E2 induction of c-myc differed. Neither acetaminophen nor E2 induced c-myc in MDA-MB-231 cells, whereas E2, but not acetaminophen, weakly induced c-myc expression in Ishikawa cells. Furthermore, in these 3 cell types, the expression patterns of the other genes differed dramatically in response to acetaminophen and to E2, indicating that acetaminophen does not activate ER as a transcription factor in the same manner as does E2. Additionally, gel shift assays demonstrated that in MCF-7 cells, acetaminophen increased NF-κB activity ∼40% and did not alter AP-1 activity, whereas E2 increased AP-1 activity ∼50% and did not increase NF-B activity. These studies indicate that acetaminophen effects on gene expression and cell proliferation depend more on cell type/context than on the presence of ER.

Original languageEnglish (US)
Pages (from-to)233-243
Number of pages11
JournalToxicological Sciences
Volume66
Issue number2
DOIs
StatePublished - Apr 17 2002

Keywords

  • Acetaminophen
  • Cell cycle
  • Estrogen receptor
  • NF-κB
  • c-myc gene

ASJC Scopus subject areas

  • Toxicology

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