Journal Article

Acetaminophen-Induced Proliferation of Estrogen-Responsive Breast Cancer Cells Is Associated with Increases in c-<i>myc</i> RNA Expression and NF-κB Activity

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

in Toxicological Sciences

Volume 66, issue 2, pages 233-243
Published in print April 2002 | ISSN: 1096-6080
Published online April 2002 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/66.2.233
Acetaminophen-Induced Proliferation of Estrogen-Responsive Breast Cancer Cells Is Associated with Increases in c-myc RNA Expression and NF-κB Activity

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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.

Keywords: acetaminophen; estrogen receptor; c-myc gene; NF-κB; cell cycle

Journal Article.  8902 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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