Estrogen-dependent rapid activation of protein kinase C in estrogen receptor-positive MCF-7 breast cancer cells and estrogen receptor-negative HCC38 cells is membrane-mediated and inhibited by tamoxifen.
We examined protein kinase C (PKC) in the regulation of breast cancer cells by estrogen. Estrogen receptor (ER)- positive (+) MCF-7 and ER-negative (-) HCC38 cells were treated with 17 beta-estradiol (E(2)) or E(2)-BSA, which cannot enter the cell. E(2) and E(2)-BSA rapidly increased PKC-alpha in both cells via phosphatidylinositol-dependent phospholipase C and G protein, but not phospholipase A(2) or arachidonic acid. In MCF-7 cells, E(2) and E(2)-BSA had comparable effects, maximal at 90 min. In HCC38 cells, PKC was maximal at 9 min, with E(2)-BSA more than E(2). Tamoxifen blocked estrogen-dependent PKC in MCF-7 cells and reduced it in HCC38 cells. ER-antagonist ICI 182780, ER-agonist diethylstilbestrol, and antibodies to ER alpha and ER beta had no effect. E(2) stimulated [(3)H]thymidine incorporation in MCF-7 only; E(2)-BSA had no effect. Tamoxifen did not alter E(2)-dependent increases in MCF-7 cells, whereas ICI 182780 reduced DNA synthesis in control and E(2)-treated cultures. PKC activity was positively correlated with tumor severity in 133 breast cancer specimens and was greater in ER(-) tumors. Tamoxifen treatment reduced recurrence, and recurrent tumors had higher PKC activity. This indicates that E(2) rapidly increases PKC activity via membrane pathways not involving ER alpha or ER beta and suggests that tamoxifen works by reducing PKC activity through non-ER alpha/ER beta-dependent mechanisms.
Boyan
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Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA. Barbara.Boyan@bme.gatech.edu
Sylvia
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Frambach
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Lohmann
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Dietl
J
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Dean
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Schwartz
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D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology; D005260:Female; D006801:Humans; D008566:Membranes; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D011960:Receptors, Estrogen; C043090:estradiol-bovine serum albumin; D013629:Tamoxifen; D012710:Serum Albumin, Bovine; D004958:Estradiol; D011493:Protein Kinase C