Summary 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'q 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) Ila/lip, cyclin A and the PKC isozyme genes (a, P,, P21 ii, 0 and j) by a cDNA-PCR approach. We found significantly enhanced mean values for MRP, LRP and PKCn gene expression, but significantly decreased Topo Ila 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 PKCr were determined: MDR1/PKC0 (rs = +0.6451, P < 0.0001) n = 62; MRPIPKCri (r, = +0.5454, P < 0.0001) n = 63; LRPIPKGYj (r, = +0.5436, P < 0.0001) n = 62; MRPILRP (rr = +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 PKCn as a possible key regulatory factor for up-regulation of a series of MDR-associated genes in different types of tumours.Keywords: Breast cancer; MDR; MDR1; MRP; LRP; PKC; topoisomerase 11The successful treatment of breast cancer using antineoplastic agents is often limited by the occurrence of drug resistance. Studies on cell lines selected in vitro revealed different mechanisms eventually responsible for the observed multidrug resistance (MDR), such as the overexpression of (a) the P-glycoprotein (P-gp) drug transporter (for review see Germann, 1996), (b) the 'multidrug resistance-associated protein' (MRP) that represents another ATP-binding cassette membrane glycoprotein also transporting drug conjugates (for review see Loe et al, 1996), (c) the 'lung cancer resistance-related protein' (LRP) that was described first in a MDR cell line lacking enhanced P-gp expression, characterized as a human major vault protein (for review see Izquierdo et al, 1996) and (4) a decreased activity of topoisomerase II (Topo II) (for review see Nitiss and Beck, 1996).An influence of protein kinase C (PKC) on P-gp-mediated MDR is suggested as well, but it still remains unclear how PKC or particular PKC isozymes might be functionally involved here: (a) in vitro studies on cell lines gave evidence that P-gp is directly