Carcinogenesis Advance Access published online on March 2, 2006
Carcinogenesis, doi:10.1093/carcin/bgl002
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1 Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
* To whom correspondence should be addressed. We previously reported that stable overexpression of protein kinase C alpha (PKC
Received September 7, 2005
Revised February 21, 2006
Accepted February 25, 2006
CANCER BIOLOGY
Overexpression of PKC
Xin Lin 1,
Yanni Yu 1,
Huiping Zhao 1,
Yiyun Zhang 1,
Jessica Manela 2,
and
Debra A. Tonetti 1 *
is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model
2 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
Debra A. Tonetti, E-mail: dtonetti{at}uic.edu
Abstract 
) in hormone responsive T47D:A18 breast cancer cells produces a hormone-independent/tamoxifen (TAM)-resistant and 17
-estradiol (E2)-inhibitory phenotype in vivo. Furthermore, overexpression of PKC in T47D:A18 cells also results in cross-upregulation of PKC and PKC
. In this study, we further characterized the contribution of PKC isozymes , , 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 PKC or to the hormone-independent/TAM-resistant and E2-inhibitory phenotype, stable T47D:A18/PKC and T47D:A18/PKC clones were established. Down regulation of PKC by shRNA in T47D:A18/PKC20 cells also resulted in reduced PKC protein expression in vitro. Tumors established from a T47D:A18/PKC/shRNA stable clone exhibit 50% reduction of PKC protein without concomitant reduction in PKC, and exhibit partial reversal of the TAM-resistant and E2-inhibitory phenotype in vivo. Furthermore, stable overexpression of neither PKC 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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