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MCF-7 cell mitogens differentially affect MAPK activation and estrogen receptor-alpha phosphorylation.

Authors
Brower-SI; Miller-MR
Source
Toxicologist 2003 Mar; 72(S-1):135
NIOSHTIC No.
20022668
Abstract
Xenoestrogens are implicated in adverse health effects by modulating the activity of the estrogen receptor (ER) either directly by binding ER or indirectly by affecting signaling pathways that impact ER activity. Estradiol (E2), epidermal growth factor (EGF) and acetaminophen (APAP) each are mitogens in MCF-7 (ER+ human breast cancer) cells, and anti-estrogens inhibit their proliferation, implying ER is involved in the mitogenic pathway(s) they activate. E2 exerts its activity by binding to and enhancing phosphorylation of ER, activating it as a transcription factor; MAPK, PKA and CaM kinase II are implicated in E2-mediated ER phosphorylation. However, EGF reportedly activates ER independent of binding by promoting ER phosphorylation through the MAPK pathway. It is unclear how APAP exerts mitogenic activity, but like EGF it does not bind ER. Therefore this study tests the hypothesis that APAP activates ER in a ligand-independent manner via MAPK activation and ER phosphorylation. MCF-7 cells served as an in vitro model in which to profile the activity of these 3 mitogens on MAPK activation and ERalpha phosphorylation, both assessed by immunoblotting. Initial studies indicated E2 enhanced MAPK activity; however additional studies clearly showed this response was an artifact caused by the addition of a small amount of stripped serum when cells were dosed with E2. MAPK is not activated when E2 is given to cells in the absence of additional serum. As previously reported, E2 also increased ERalpha phosphorylation. In contrast, EGF transiently and robustly induced MAPK activation, but did not increase ERalpha phosphorylation. Unlike E2 and EGF, APAP had no effect on either MAPK activity or ERalpha phosphorylation. These findings indicate ER has complex involvement in MCF-7 cell growth, and estrogenic compounds can induce ER-mediated breast cancer cell proliferation through various signaling pathways. Additional studies are needed to determine what kinase(s) are responsible for E2-induced ERalpha phosphorylation, as it is clear from this study that MAPK is not activated above basal levels by E2.
Keywords
Growth-factors; Cell-growth; Cell-cultures; Cell-damage; Cancer; Cancer-rates
Publication Date
20030301
Document Type
Abstract
Fiscal Year
2003
NTIS Accession No.
NTIS Price
ISSN
1096-6080
NIOSH Division
HELD
Priority Area
Disease and Injury: Fertility and Pregnancy Abnormalities
Source Name
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah
State
WV
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