Carcinogenesis Advance Access originally published online on March 2, 2006
Carcinogenesis 2006 27(8):1538-1546; doi:10.1093/carcin/bgl002
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Overexpression of PKC
is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model
Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago Chicago, IL, USA
1 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Chicago, IL, USA
*To whom correspondence should be addressed at: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street (M/C 865), Chicago, IL 60612, USA. Tel: +1 312 413 1169; Fax: +1 312 996 1698; Email: dtonetti{at}uic.edu
We previously reported that stable overexpression of protein kinase C alpha (PKC
) in hormone responsive T47D:A18 breast cancer cells produces a hormone-independent/tamoxifen (TAM)-resistant and 17ß-estradiol (E2)-inhibitory phenotype in vivo. Furthermore, overexpression of PKC in T47D:A18 cells also results in cross-upregulation of PKCs ß and 
. In this study, we further characterized the contribution of PKC isozymes , ß and to this complex phenotype. To determine whether downregulation of PKC is sufficient to restore the hormone-dependent phenotype in T47D:A18/PKC cells, PKC was selectively knocked down using short hairpin RNA (shRNA). To determine the contribution of PKCß or to the hormone-independent/TAM-resistant and E2-inhibitory phenotype, stable T47D:A18/PKCß and T47D:A18/PKC clones were established. Downregulation of PKC by shRNA in T47D:A18/PKC20 cells also resulted in reduced PKCß protein expression in vitro. Tumors established from a T47D:A18/PKC/shRNA stable clone exhibit 50% reduction of PKC protein without concomitant reduction in PKCß, and exhibit partial reversal of the TAM-resistant and E2-inhibitory phenotype in vivo. Furthermore, stable overexpression of neither PKCß nor PKC in T47D:A18 cells are sufficient to produce hormone-independent growth in vitro or in vivo, nor TAM-resistant and E2-inhibited growth in vivo. Taken together, these results suggest that PKC is required to impart the TAM-resistant and E2-inhibitory phenotype in vivo.
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