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Archives of Medical Science
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vol. 13
Basic research

Expression of multidrug resistance protein P-glycoprotein in correlation with markers of hypoxia (HIF-1α, EPO, EPO-R) in invasive breast cancer with metastasis to lymph nodes

Anna M. Badowska-Kozakiewicz, Maria Sobol, Janusz Patera

Arch Med Sci 2017; 13, 6: 1303–1314
Online publish date: 2016/10/18
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Introduction: Overexpression of the mdr-1 gene is the earliest discovered mechanism of multidrug resistance, which is associated with P-glycoprotein (P-gp) – a cell membrane protein responsible for the efflux of drugs of various structures out of cancer cells. Although the expression of P-glycoprotein has been demonstrated in many cancer types, its relation to markers of hypoxia such as HIF-1α, EPO-R or EPO in invasive breast cancer is not well established. The aim of this research was to analyze the co-expression of P-glycoprotein and the markers of tissue hypoxia HIF-1α, EPO, and EPO-R by immunohistochemistry in invasive breast cancer classified according to the presence of steroid receptors and the HER2 receptors.

Material and methods: Tissue samples were collected from 58 patients with the diagnosis of invasive breast cancer with lymph node metastases. The expression of P-gp, HIF-1α, EPO-R and EPO was determined by immunohistochemistry.

Results: Of all the invasive breast cancers with lymph node metastases, 15.5% expressed P-gp in cell membrane and tumor blood vessels. In our research, there was a significant positive correlation between HER2-positive tumors that did not express steroid receptors (ER–/PR–/HER2+), and P-gp expression (p = 0.049, r = 0.105). Moreover, there was a significant positive correlation between EPO expression and P-gp (p < 0.001, r = 0.474), and between HIF-1α expression and P-gp (p = 0.00475, r = 0.371).

Conclusions: We found that HIF-1α and EPO expression is significantly associated with P-gp expression in invasive breast cancer with lymph node metastases. An important result of our study is the demonstration of a correlation between P-gp expression and patients with HER2-positive breast tumors that do not express steroid receptors.

P-glycoprotein, markers of hypoxia, invasive breast cancers with lymph node metastases

Faneyte IF, Kristel PM, Maliepaard M, et al. Expression of the breast cancer resistance protein in breast cancer. Clin Cancer Res 2002; 8: 1068-74.
Zhai X, Wang H, Zhu X, et al. Gene polymorphisms of ABC transporters are associated with clinical outcomes in children with acute lymphoblastic leukemia. Arch Med Sci 2012; 8: 659-71.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
Borowski E, Bontemps-Gracz M, Piwkowska A. Strategies for ovecoming ABC-transporters-mediated multidrug resistance (MDR) of tumor cells. Acta Biochemica Polonica 2005; 5: 609-27.
Ling V. Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol 1997; 40: 3-8.
Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. Oncolgist 2003; 8: 411-24.
Locher KP. Structure and mechanism of ABC transporters. Curr Opin Struct Biol 2004; 14: 426-31.
Gottesmann MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53: 615-27.
Gottesmann MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2: 48-58.
Parissenti AM, Gannan BR, Villeneuve DJ, Kirwan-Rhude AF, Chadderton A, Gluck S. Lack of modulation of MDR1 gene expression by dominant inhibition of cAMP-dependet protein kinase in doxorubicin-resistant MCF-7 breast cancer cells. Int J Cancer 1999; 82: 893-900.
Veneroni S, Zaffaroni N, Daidone MG, Benini E, Villa R, Silvestrini R. Expression of P-glycoprotein and in vitro or in vivo resistance to doxorubicin and cisplatin in breast and ovarian cancers. Eur J Cancer 1994; 30A: 1002-7.
Xia Z, Zhu Z, Zhang L, et al. Specific reversal of MDR1/P-gp-dependent multidrug resistance by RNA interference in colon cancer cells. Oncol Rep 2008; 20: 1433-9.
Zhang Y, Ski Y, Li X, et al. Proteasome inhibitor MG 132 reverses multidrug resistance of gastric cancer through enhancing apoptosis and inhibiting P-gp. Cancer Biol Ther 2008; 7: 540-6.
Gruber G, Greiner RH, Hlushchuk R, et al. Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter? Breast Cancer Res 2004; 6: R191-8.
Wang L, Li HG, Xia ZS. Prognostic significance of erythropoietin and erythropoietin receptor in gastric adenocarcinoma. World J Gastroentero 2011; 17: 3933-40.
Silov G, Erdoğan Z, Özdal A, et al. The value of Tc-99m tetrofosmin scintimammography in the assessment of P-glycoprotein in patients with breast cancer. Hell J Nucl Med 2013; 16: 218-22.
Young LC, Campling BG, Voskoglou-Nomikos T, Cole SP, Deeley RG, Gerlach JH. Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response. Clin Cancer Res 1999; 5: 673-80.
Galimberti S, Marchetti A, Buttitta F, et al. Multidrug resistance related genes and p53 expression in human non small cell lung cancer. Anticancer Res 1998; 18: 2973-6.
Clifford SC, Neal DE, Lunec J. High level expression of themultidrug resistance (MDR1) gene in the normal bladder urothelium: a potential involvement in protection against carcinogens? Carcinogenesis 1996; 17: 601-4.
Nakagawa M, Emoto A, Nasu N, et al. Clinical significance of multi-drug resistance associated protein and P-glycoprotein in patients with bladder cancer. J Urol 1997; 157: 1260-4.
Park J, Shinohara N, Liebert M, Noto L, Flint A, Grossman HB. P-glycoprotein expression in bladder cancer. J Urol 1994; 151: 43-6.
Joly F, Mangioni C, Nicoletto M. A phase 3 study of PSC 833 in combination with paclitaxel and carboplatin (PC-PSC) versus paclitaxel and carboplatin (PC) alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary cancer of the peritoneum. Proc Am Soc Clin Oncol 2002; 21: 202a.
Burger H, Foekens JA, Look MP, et al. RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response. Clin Cancer Res 2003; 9: 827-36.
Turkina AG, Logacheva NP, Stromskaya TP, et al. Studies of some mechanisms of drug resistance in chronic myeloid leukemia (CML). Adv Exp Med Biol 1999; 457: 477-88.
Trock BJ, Leonessa F. Clarke R. Multidrug resistance in breast cancer: a meta-analysis MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 1997; 89: 917-31.
Decker DA, Morris LW, Levine AJ, Pettinga JE, Grudzien JL, Farkas DH. Immunohistochemical analysis of P-glycoprotein expression in breast cancer: clinical correlations. Ann Clin Lab Sci 1995; 25: 52-9.
Chung HC, Rha SY, Kim JH, et al. P-glycoprotein: the intermediate end point of drug response to induction chemotherapy in locally advanced breast cancer. Breast Cancer Res Treat 1997; 42: 65-72.
Chevillard S, Pouillart P, Beldjord C, et al. Sequential assessment of multidrug resistance phenotype and measurement of S-phase fraction as predictive markers of breast cancer response to neoadjuvant chemotherapy. Cancer 1996; 77: 292-300.
Ding Z, Yang L, Xie X, et al. Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. J Cancer Res Clin Oncol 2010; 136: 1697-707.
Zhu H, Chen XP, Luo SF, Guan J, Zhang WG, Zhang BX. Involvement of hypoxia-inducible factor-1 alpha in multidrug resistance induced by hypoxia in HepG2 cells. J Exp Clin Cancer Res 2005; 24: 565-74.
Lv Y, Zhao S, Han J, Zheng L, Yang Z, Zhao L. Hypoxia-inducible factor-1alpha induces multidrug resistance protein in colon cancer. Onco Targets Ther 2015; 8: 1941-8.
Tsukamoto F, Shiba E, Taguchi T, et al. Immunohistochemical detection of P-glycoprotein in breast cancer and its significance as a prognostic factor. Breast Cancer 1997; 4: 259-63.
Li EX, Li R, Zhang ZH, Wang JB. Clinical significance of P-glycoprotein expression in breast cancer. Chin J Cancer Res 1999; 11: 218-20.
Leong AS, Raymond WA. Prognostic parameters in breast cancer. Pathology 1989; 21: 169-75.
Tang Y, Wang Y, Deosarkar S, Soroush F, Kiani MF, Wang B. Fast, stable induction of P-glycoprotein-mediated drug resistance in BT-474 breast cancer cells by stable transfection of ABCB1 gene. Anticancer Res 2015; 35: 2531-8.
Doublier S, Belisario DC, Polimeni M, et al. HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast. BMC Cancer 20124; 12: 4.
Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E. Hypoxia and defective apoptosis drive genomic instability and tumorogenesis. Genes Development 2004; 18: 2095-107.
Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto SP, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002; 62: 3387-94.
Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 2007; 99: 1441-54.
Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M. Tumor hypoxia: a target for selective cancer therapy. Cancer Sci 2003; 94: 1021-8.
Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev 2003; 29: 297-307.
Lehnert M. Chemotherapy resistance in breast cancer. Anticancer Res 1998; 18: 2225-6.
Belpomme D, Gauthier S, Pujade-Lauraine E, et al. Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma. Ann Oncol 2000; 11: 1471-6.
Baer MR. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood 2002; 100: 1224-32.
Kolitz JE. Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621. J Clin Oncol 2004; 22: 4290-301.
Guns ES, Denyssevych T, Dixon R, Bally MB, Mayer L. Drug interaction studies between paclitaxel (Taxol) and OC144-093 – a new modulator of MDR in cancer chemotherapy. Eur J Drug Metabol Pharmacokinet 2002; 27: 119-26.
Dantzig AH, de Alwis DP, Burgess M. Considerations in the design and development of transport inhibitors as adjuncts to drug therapy. Adv Drug Deliv Rev 2003; 55: 133-50.
Zhou S, Lim LY, Chowbay B. Herbal modulation of P-glycoprotein. Drug Metabol Rev 2004; 36: 57-104.
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