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We previously reported that stable overexpression of protein kinase C alpha (PKCα) in hormone responsive T47D:A18 breast cancer cells produces a hormone-independent/tamoxifen (TAM)-resistant and 17β-estradiol (E2)-inhibitory phenotypein vivo. Furthermore, overexpression of PKCα in T47D:A18 cells also results in cross-upregulation of PKCs β and δ. In this study, we further characterized the contribution of PKC isozymes α, β and δ to this complex phenotype. To determine whether downregulation of PKCα is sufficient to restore the hormone-dependent phenotype in T47D:A18/PKCα cells, PKCα was selectively knocked down using short hairpin RNA (shRNA). To determine the contribution of PKCβ or δ to the hormone-independent/TAM-resistant and E2-inhibitory phenotype, stable T47D:A18/PKCβ and T47D:A18/PKCδ clones were established. Downregulation of PKCα by shRNA in T47D:A18/PKCα20 cells also resulted in reduced PKCβ protein expressionin vitro. Tumors established from a T47D:A18/PKCα/shRNA stable clone exhibit 50% reduction of PKCα protein without concomitant reduction in PKCβ, and exhibit partial reversal of the TAM-resistant and E2-inhibitory phenotypein vivo. Furthermore, stable overexpression of neither PKCβ nor PKCδ in T47D:A18 cells are sufficient to produce hormone-independent growthin vitroorin vivo, nor TAM-resistant and E2-inhibited growthin vivo. Taken together, these results suggest that PKCα is required to impart the TAM-resistant and E2-inhibitory phenotypein vivo.

Overexpression of PKCα is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model