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Protein kinase C beta enhances growth and expression of cyclin D1 in human breast cancer cells.
Cancer Res. 2006 Dec 01; 66(23):11399-408.CR

Abstract

Although alterations in the expressions of protein kinase C (PKC) have been implicated in breast carcinogenesis, the roles of specific isoforms in this process remain elusive. In the present study, we examined the specific roles of PKCbeta1 and beta2 in growth control in human breast cancer cell lines. The PKCbeta-specific inhibitor LY379196 significantly inhibited growth of the breast cancer cell lines MCF-7, MDA-MB-231, and BT474, but not the normal mammary epithelial cell line MCF-10F. Treatment of MCF-7 cells with LY379196 caused an increase in the fraction of cells in the G(1) phase of the cell cycle. To explore the roles of PKCbeta1 and beta2, we used cDNA expression vectors that encode wild-type and constitutively activated or dominant negative mutants of these two proteins. When compared with vector controls, derivatives of MCF-7 cells that stably overexpress wild-type PKCbeta1 or PKCbeta2 displayed a slight increase in growth rate; derivatives that stably express the constitutively active mutants of PKCbeta1 or PKCbeta2 displayed a marked increase in growth rate; and derivatives that stably express a dominant negative mutant of PKCbeta1 or beta2 displayed inhibition of growth. The derivatives of MCF-7 cells that stably express the constitutively activated mutants of PKCbeta1 or beta2 were more resistant to growth inhibition by LY379196 than the vector control MCF-7 cells. Immunoblot analysis indicated that MCF-7 cells that stably overexpress wild-type or constitutively activated mutants of PKCbeta1 or beta2 had higher cellular levels of cyclin D1 than vector control cells, whereas cells that express a dominant negative mutant had decreased levels of cyclin D1. The derivatives that stably express the constitutively activated mutants of PKCbeta1 or beta2 also displayed increased cyclin D1 promoter activity in transient transfection luciferase reporter assays, and this induction of activity requires activator protein 1. Constitutively activated PKCbeta1 and beta2 also enhanced the transcription of c-fos in transient transfection luciferase reporter assays. Thus, PKCbeta1 and beta2 may play important positive roles in the growth of at least a subset of human breast cancers. Therefore, inhibitors of these isoforms may be useful in breast cancer chemoprevention or therapy.

Authors+Show Affiliations

Herbert Irving Comprehensive Cancer Center, Department of Medicine, Columbia University, New York, New York 10032, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17145886

Citation

Li, Haiyang, and I Bernard Weinstein. "Protein Kinase C Beta Enhances Growth and Expression of Cyclin D1 in Human Breast Cancer Cells." Cancer Research, vol. 66, no. 23, 2006, pp. 11399-408.
Li H, Weinstein IB. Protein kinase C beta enhances growth and expression of cyclin D1 in human breast cancer cells. Cancer Res. 2006;66(23):11399-408.
Li, H., & Weinstein, I. B. (2006). Protein kinase C beta enhances growth and expression of cyclin D1 in human breast cancer cells. Cancer Research, 66(23), 11399-408.
Li H, Weinstein IB. Protein Kinase C Beta Enhances Growth and Expression of Cyclin D1 in Human Breast Cancer Cells. Cancer Res. 2006 Dec 1;66(23):11399-408. PubMed PMID: 17145886.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase C beta enhances growth and expression of cyclin D1 in human breast cancer cells. AU - Li,Haiyang, AU - Weinstein,I Bernard, PY - 2006/12/6/pubmed PY - 2007/1/11/medline PY - 2006/12/6/entrez SP - 11399 EP - 408 JF - Cancer research JO - Cancer Res VL - 66 IS - 23 N2 - Although alterations in the expressions of protein kinase C (PKC) have been implicated in breast carcinogenesis, the roles of specific isoforms in this process remain elusive. In the present study, we examined the specific roles of PKCbeta1 and beta2 in growth control in human breast cancer cell lines. The PKCbeta-specific inhibitor LY379196 significantly inhibited growth of the breast cancer cell lines MCF-7, MDA-MB-231, and BT474, but not the normal mammary epithelial cell line MCF-10F. Treatment of MCF-7 cells with LY379196 caused an increase in the fraction of cells in the G(1) phase of the cell cycle. To explore the roles of PKCbeta1 and beta2, we used cDNA expression vectors that encode wild-type and constitutively activated or dominant negative mutants of these two proteins. When compared with vector controls, derivatives of MCF-7 cells that stably overexpress wild-type PKCbeta1 or PKCbeta2 displayed a slight increase in growth rate; derivatives that stably express the constitutively active mutants of PKCbeta1 or PKCbeta2 displayed a marked increase in growth rate; and derivatives that stably express a dominant negative mutant of PKCbeta1 or beta2 displayed inhibition of growth. The derivatives of MCF-7 cells that stably express the constitutively activated mutants of PKCbeta1 or beta2 were more resistant to growth inhibition by LY379196 than the vector control MCF-7 cells. Immunoblot analysis indicated that MCF-7 cells that stably overexpress wild-type or constitutively activated mutants of PKCbeta1 or beta2 had higher cellular levels of cyclin D1 than vector control cells, whereas cells that express a dominant negative mutant had decreased levels of cyclin D1. The derivatives that stably express the constitutively activated mutants of PKCbeta1 or beta2 also displayed increased cyclin D1 promoter activity in transient transfection luciferase reporter assays, and this induction of activity requires activator protein 1. Constitutively activated PKCbeta1 and beta2 also enhanced the transcription of c-fos in transient transfection luciferase reporter assays. Thus, PKCbeta1 and beta2 may play important positive roles in the growth of at least a subset of human breast cancers. Therefore, inhibitors of these isoforms may be useful in breast cancer chemoprevention or therapy. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/17145886/Protein_kinase_C_beta_enhances_growth_and_expression_of_cyclin_D1_in_human_breast_cancer_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17145886 DB - PRIME DP - Unbound Medicine ER -