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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

Wallace H. Coulter Department of Biomedical Engineering (B.D.B., Z.S.), Georgia Institute of Technology, Atlanta, Georgia 30332; Departments of Periodontics (Z.S.) and Orthopaedics (V.L.S., D.D.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Department of Gynecology (T.F., J.D.), University of Würzburg, 97070 Würzburg, Germany; Department of Orthopedics (C.H.L.), University of Eppendorf, 20255 Hamburg, Germany; and Department of Periodontics (Z.S.), Hebrew University Hadassah, Jerusalem 91120, Israel

Address all correspondence and requests for reprints to: Barbara D. Boyan, Ph.D., Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332. E-mail: Barbara.Boyan{at}bme.gatech.edu.

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 17ß-estradiol (E₂) or E₂-BSA, which cannot enter the cell. E₂ and E₂-BSA rapidly increased PKC- in both cells via phosphatidylinositol-dependent phospholipase C and G protein, but not phospholipase A₂ or arachidonic acid. In MCF-7 cells, E₂ and E₂-BSA had comparable effects, maximal at 90 min. In HCC38 cells, PKC was maximal at 9 min, with E₂-BSA more than E₂. 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 and ERß had no effect. E₂ stimulated [³H]thymidine incorporation in MCF-7 only; E₂-BSA had no effect. Tamoxifen did not alter E₂-dependent increases in MCF-7 cells, whereas ICI 182780 reduced DNA synthesis in control and E₂-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 E₂ rapidly increases PKC activity via membrane pathways not involving ER or ERß and suggests that tamoxifen works by reducing PKC activity through non-ER/ERß-dependent mechanisms.

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