title: Role of MAP kinase in the enhanced cell proliferation of long term estrogen deprived human breast cancer cells.
abstract: Women with estrogen receptor (ER) positive breast cancers frequently respond initially to inhibition of estrogen action but later relapse with re-growth of tumor. Previously, we have utilized MCF-7 human breast cancer cells deprived of estradiol long term (LTED cells) as the model system to study the regrowth phenomenon and have demonstrated that these cells exhibited increased cell proliferation rate and increased ER functionality during the adaptive processes. In this report, we examined the hypothesis that the mitogen-activated protein kinase (MAP kinase) signal was involved. We found that activated MAP kinase was elevated in LTED cells and that the MAP kinase specific inhibitor PD98059 was able to inhibit the elevated MAP kinase and [3H]thymidine uptake in LTED cells, suggesting mediation of DNA synthesis and proliferation by the MAP kinase pathway. Other MAP kinase upstream inhibitors, including genestein, RG13022, and mevastatin were also able to inhibit the [3H]thymidine uptake in LTED cells. Interestingly, the antiestrogen, ICI 182,780 was able to block the activated MAP kinase in LTED cells. Treatment with PD98059 did not block elevated basal ERE-CAT activity while at the same time inhibiting [3H]thymidine uptake in LTED cells. Furthermore, treatment with PD98059 partially blocked the E2-stimulated ERE-CAT activity and [3H]thymidine uptake in both LTED and in wild type cells, indicating that both MAP kinase-dependent and MAP kinase-independent pathways are involved in the transactivation function of ER. Taken together, our data suggest that the MAP kinase pathway is, in part, involved in the adaptive process which results in enhanced DNA synthesis and cell proliferation in the absence of exogenous estrogen in LTED cells.
authors.affiliation: Department of Internal Medicine, University of Virginia Health System, Charlottesville, USA. mjeng@iupui.edu
authors.forename: M H
authors.initials: MH
authors.lastname: Jeng
authors.forename: W
authors.initials: W
authors.lastname: Yue
authors.forename: A
authors.initials: A
authors.lastname: Eischeid
authors.forename: J P
authors.initials: JP
authors.lastname: Wang
authors.forename: R J
authors.initials: RJ
authors.lastname: Santen
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D005419:Flavonoids; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D013936:Thymidine