Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue.

Abstract

Because of their central role in the transduction of extracellular signals, protein kinases A (PKA) and C (PKC) are critical enzymes in the control of cellular proliferation and differentiation. We have measured the catalytic activity of PKA and PKC, as well as the regulatory subunit expression for PKA, in paired samples of normal and malignant breast tissue from 13 patients with breast cancer. Paired non-parametric (Wilcoxon) analysis revealed significantly higher values for both basal (P = 0.0002) and total (P = 0.0002) PKA catalytic activity in malignant compared with normal breast in all 13 paired tissue samples. Expression of both R1- and RII-PKA regulatory subunits were also higher in malignant tissue from 12 (P = 0.0005) and 9 (P = 0.01) of the 13 pairs, respectively. However, the degree of RI-subunit overexpression in malignant tissue was greater than that of the RII-subunit, as demonstrated by an increase in the RI/RII subunit ratio in 10 of the 13 paired samples (P = 0.017). Total PKC catalytic activity was elevated in 11 of the 13 malignant tissue specimens when compared with corresponding normal breast tissue (P = 0.01). This was accounted for by an increase in Ca(2+)-dependent PKC activity (P = 0.01), there being no significant increase in Ca(2+)-independent PKC activity. These data suggest that the activities of both PKA and PKC signalling pathways are intrinsically higher in malignant compared with normal breast tissue and these may therefore represent targets for interventive treatment of breast cancer.