Protein kinase C δ enhances proliferation and survival of murine mammary cells

Protein kinase C (PKC) delta, a member of the novel family of PKC serine-threonine kinases, has been implicated in negative regulation of proliferation and apoptosis in a large number of cell types, including breast cancer cell lines, and postulated as a tumor suppressor gene. In this study we show that in murine NMuMG mammary cells PKC delta promotes a mitogenic response. Overexpression of PKC delta in NMuMG cells leads to a significant increase in [H-3]-tymidine incorporation and cell proliferation, as well as enhanced extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation. Activation of PKC delta with a phorbol ester leads to elevated cyclin D1 expression and an hyperphosphorylated Rb state. Surprisingly, ectopic expression of PKC delta conferred anchorage-independent growth capacity to NMuMG cells. PKC delta overexpressors showed enhanced resistance to apoptotic stimuli, such as serum deprivation or doxorubicin treatment, an effect that correlates with hyperactivation of the Akt survival pathway. Our results provide evidence for a role of PKC delta as a positive modulator of proliferative and survival signals in immortalized mammary cells. The fact that PKC delta exerts differential responses depending on the cell context not only highlights the necessity to carefully understand the signaling events controlled by this PKC in each cell type but also suggests that we should be cautious in considering this kinase a target for cancer therapy. (c) 2007 Wiley-Liss, Inc.