A possible link between
protein kinase C (PKC) and
P-glycoprotein (P-gp)-mediated-multidrug resistance (MDR) was assumed from studies on MDR cell lines selected in vitro. The functional relevance of PKC for the MDR phenotype remains unclear, and the involvement of a particular PKC
isozyme in clinically occurring drug resistance is not known. Recently, we have demonstrated significant correlations between the expression levels of the
PKC eta isozyme and the MDR1 or MRP (
multidrug resistance-associated protein) genes in blasts from patients with acute myelogenous leukaemia (AML) and in
ascites cell aspirates from
ovarian cancer patients. To extend these findings to further types of human tumours we analysed specimens from 64 patients with primary
breast cancer for their individual expression levels of several MDR-associated genes (MDR1, MRP, LRP (
lung cancer resistance-related
protein), topoisomerase (
Topo) II alpha/IIbeta,
cyclin A and the PKC
isozyme genes (alpha, beta1, beta2, eta, theta, and mu) by a
cDNA-PCR approach. We found significantly enhanced mean values for MRP, LRP and
PKC eta gene expression, but significantly decreased
Topo II alpha and
cyclin A gene expression levels in G2 tumours compared with G3. Remarkably, significant positive correlations between the MDR1, MRP or LRP gene expression levels and
PKC eta were determined: MDR1/
PKC eta (rs = +0.6451, P < 0.0001) n = 62; MRP/
PKC eta (rs = +0.5454, P < 0.0001) n = 63; LRP/
PKC eta (rs = +0.5436, P < 0.0001) n = 62; MRP/LRP (rs = +0.7703, P < 0.0001) and n = 62, MDR1/MRP (rs = +0.5042, P < 0.0001) n = 62. Our findings point to the occurrence of a multifactorial MDR in the clinics and to
PKC eta as a possible key regulatory factor for up-regulation of a series of MDR-associated genes in different types of tumours.