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British Journal of Cancer logoLink to British Journal of Cancer
. 1998;77(1):87–91. doi: 10.1038/bjc.1998.13

Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlations of PKC eta with MDR1, MRP and LRP gene expression.

J Beck 1, B Bohnet 1, D Brügger 1, P Bader 1, J Dietl 1, R J Scheper 1, R Kandolf 1, C Liu 1, D Niethammer 1, V Gekeler 1
PMCID: PMC2151261  PMID: 9459150

Abstract

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.

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Selected References

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  1. BLOOM H. J., RICHARDSON W. W. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957 Sep;11(3):359–377. doi: 10.1038/bjc.1957.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Batist G., Tulpule A., Sinha B. K., Katki A. G., Myers C. E., Cowan K. H. Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells. J Biol Chem. 1986 Nov 25;261(33):15544–15549. [PubMed] [Google Scholar]
  3. Beck J., Handgretinger R., Dopfer R., Klingebiel T., Niethammer D., Gekeler V. Expression of mdr1, mrp, topoisomerase II alpha/beta, and cyclin A in primary or relapsed states of acute lymphoblastic leukaemias. Br J Haematol. 1995 Feb;89(2):356–363. doi: 10.1111/j.1365-2141.1995.tb03312.x. [DOI] [PubMed] [Google Scholar]
  4. Beck J., Handgretinger R., Klingebiel T., Dopfer R., Schaich M., Ehninger G., Niethammer D., Gekeler V. Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML. Leukemia. 1996 Mar;10(3):426–433. [PubMed] [Google Scholar]
  5. Blobe G. C., Obeid L. M., Hannun Y. A. Regulation of protein kinase C and role in cancer biology. Cancer Metastasis Rev. 1994 Dec;13(3-4):411–431. doi: 10.1007/BF00666107. [DOI] [PubMed] [Google Scholar]
  6. Chambers T. C., McAvoy E. M., Jacobs J. W., Eilon G. Protein kinase C phosphorylates P-glycoprotein in multidrug resistant human KB carcinoma cells. J Biol Chem. 1990 May 5;265(13):7679–7686. [PubMed] [Google Scholar]
  7. Chaudhary P. M., Roninson I. B. Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst. 1993 Apr 21;85(8):632–639. doi: 10.1093/jnci/85.8.632. [DOI] [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Clifford S. C., Neal D. E., Lunec J. Alterations in expression of the multidrug resistance-associated protein (MRP) gene in high-grade transitional cell carcinoma of the bladder. Br J Cancer. 1996 Mar;73(5):659–666. doi: 10.1038/bjc.1996.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cordell J. L., Falini B., Erber W. N., Ghosh A. K., Abdulaziz Z., MacDonald S., Pulford K. A., Stein H., Mason D. Y. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984 Feb;32(2):219–229. doi: 10.1177/32.2.6198355. [DOI] [PubMed] [Google Scholar]
  11. Gekeler V., Boer R., Ise W., Sanders K. H., Schächtele C., Beck J. The specific bisindolylmaleimide PKC-inhibitor GF 109203X efficiently modulates MRP-associated multiple drug resistance. Biochem Biophys Res Commun. 1995 Jan 5;206(1):119–126. doi: 10.1006/bbrc.1995.1017. [DOI] [PubMed] [Google Scholar]
  12. Gekeler V., Boer R., Uberall F., Ise W., Schubert C., Utz I., Hofmann J., Sanders K. H., Schächtele C., Klemm K. Effects of the selective bisindolylmaleimide protein kinase C inhibitor GF 109203X on P-glycoprotein-mediated multidrug resistance. Br J Cancer. 1996 Sep;74(6):897–905. doi: 10.1038/bjc.1996.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gekeler V., Frese G., Diddens H., Probst H. Expression of a P-glycoprotein gene is inducible in a multidrug-resistant human leukemia cell line. Biochem Biophys Res Commun. 1988 Sep 15;155(2):754–760. doi: 10.1016/s0006-291x(88)80559-x. [DOI] [PubMed] [Google Scholar]
  14. Germann U. A., Chambers T. C., Ambudkar S. V., Licht T., Cardarelli C. O., Pastan I., Gottesman M. M. Characterization of phosphorylation-defective mutants of human P-glycoprotein expressed in mammalian cells. J Biol Chem. 1996 Jan 19;271(3):1708–1716. doi: 10.1074/jbc.271.3.1708. [DOI] [PubMed] [Google Scholar]
  15. Germann U. A. P-glycoprotein--a mediator of multidrug resistance in tumour cells. Eur J Cancer. 1996 Jun;32A(6):927–944. doi: 10.1016/0959-8049(96)00057-3. [DOI] [PubMed] [Google Scholar]
  16. Goldstein L. J., Galski H., Fojo A., Willingham M., Lai S. L., Gazdar A., Pirker R., Green A., Crist W., Brodeur G. M. Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst. 1989 Jan 18;81(2):116–124. doi: 10.1093/jnci/81.2.116. [DOI] [PubMed] [Google Scholar]
  17. Greif H., Ben-Chaim J., Shimon T., Bechor E., Eldar H., Livneh E. The protein kinase C-related PKC-L(eta) gene product is localized in the cell nucleus. Mol Cell Biol. 1992 Mar;12(3):1304–1311. doi: 10.1128/mcb.12.3.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Izquierdo M. A., Scheffer G. L., Flens M. J., Schroeijers A. B., van der Valk P., Scheper R. J. Major vault protein LRP-related multidrug resistance. Eur J Cancer. 1996 Jun;32A(6):979–984. doi: 10.1016/0959-8049(96)00053-6. [DOI] [PubMed] [Google Scholar]
  19. Loe D. W., Deeley R. G., Cole S. P. Biology of the multidrug resistance-associated protein, MRP. Eur J Cancer. 1996 Jun;32A(6):945–957. doi: 10.1016/0959-8049(96)00046-9. [DOI] [PubMed] [Google Scholar]
  20. Nitiss J. L., Beck W. T. Antitopoisomerase drug action and resistance. Eur J Cancer. 1996 Jun;32A(6):958–966. doi: 10.1016/0959-8049(96)00056-1. [DOI] [PubMed] [Google Scholar]
  21. Pines J., Hunter T. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature. 1990 Aug 23;346(6286):760–763. doi: 10.1038/346760a0. [DOI] [PubMed] [Google Scholar]
  22. Ro J., Sahin A., Ro J. Y., Fritsche H., Hortobagyi G., Blick M. Immunohistochemical analysis of P-glycoprotein expression correlated with chemotherapy resistance in locally advanced breast cancer. Hum Pathol. 1990 Aug;21(8):787–791. doi: 10.1016/0046-8177(90)90046-8. [DOI] [PubMed] [Google Scholar]
  23. Sanfilippo O., Ronchi E., De Marco C., Di Fronzo G., Silvestrini R. Expression of P-glycoprotein in breast cancer tissue and in vitro resistance to doxorubicin and vincristine. Eur J Cancer. 1991;27(2):155–158. doi: 10.1016/0277-5379(91)90476-t. [DOI] [PubMed] [Google Scholar]
  24. Sato W., Yusa K., Naito M., Tsuruo T. Staurosporine, a potent inhibitor of C-kinase, enhances drug accumulation in multidrug-resistant cells. Biochem Biophys Res Commun. 1990 Dec 31;173(3):1252–1257. doi: 10.1016/s0006-291x(05)80921-0. [DOI] [PubMed] [Google Scholar]
  25. Scala S., Dickstein B., Regis J., Szallasi Z., Blumberg P. M., Bates S. E. Bryostatin 1 affects P-glycoprotein phosphorylation but not function in multidrug-resistant human breast cancer cells. Clin Cancer Res. 1995 Dec;1(12):1581–1587. [PubMed] [Google Scholar]
  26. Schneider J., Bak M., Efferth T., Kaufmann M., Mattern J., Volm M. P-glycoprotein expression in treated and untreated human breast cancer. Br J Cancer. 1989 Dec;60(6):815–818. doi: 10.1038/bjc.1989.372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yu G., Ahmad S., Aquino A., Fairchild C. R., Trepel J. B., Ohno S., Suzuki K., Tsuruo T., Cowan K. H., Glazer R. I. Transfection with protein kinase C alpha confers increased multidrug resistance to MCF-7 cells expressing P-glycoprotein. Cancer Commun. 1991 Jun;3(6):181–189. doi: 10.3727/095535491820873263. [DOI] [PubMed] [Google Scholar]

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