Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Expression and localisation of breast cancer resistance protein (BCRP) in human fetal membranes and decidua and the influence of labour at term

D. Yeboah A , G. M. Kalabis B , M. Sun A , R. C. Ou A , S. G. Matthews B D and W. Gibb A C

A Department of Obstetrics and Gynecology and Cellular and Molecular Medicine, University of Ottawa, Ontario K1H8M5, Canada.

B Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada.

C Ottawa Health Research Institute, Ottawa Hospital, Ottawa, Ontario K1H8L6, Canada.

D Corresponding author. Email: stephen.matthews@utoronto.ca

Reproduction, Fertility and Development 20(2) 328-334 https://doi.org/10.1071/RD07133
Submitted: 12 August 2007  Accepted: 6 December 2007   Published: 24 January 2008

Abstract

Breast cancer resistance protein (BCRP) is a multidrug resistant ABC transport protein (ABCG-2). It extrudes a wide range of substrates, including many chemotherapy drugs, steroids and folate. It is present in many cancers, as well as normal tissues, in particular barrier tissues such as the blood–brain barrier, the intestine, blood vessels and the human placenta. Human fetal membranes (amnion and chorion laeve) provide the barrier between the maternal uterine environment and the fetus. In the present study, we defined the expression and localisation of BCRP mRNA and protein in human fetal membranes (amnion and chorion) and attached decidua obtained before and following labour at term. BCRP protein and mRNA was expressed in all tissues examined and the levels of expression were not altered by labour. BCRP was localised to the amnion epithelial cells, chorion trophoblast cells and decidua stromal cells, as well as the endothelial cells of maternal blood vessels in the decidua, but was absent from mesenchymal cells. In the amnion epithelium, BCRP protein was localised to the apical surface, cytoplasm and membrane between cells. In the chorion trophoblast and decidua stromal cells, BCRP protein was localised to the plasma membrane. However, in the chorion trophoblast, BCRP protein was also highly expressed in the nucleus. The level of BCRP protein in the membranes was comparable to that in the placenta. These high levels raise the possibility that this transporter plays an important role in the physiological function of the tissues.


Acknowledgements

This study was funded by the Canadian Institutes for Health Research (FRN-57746; to S.G.M. and W.G.) and a scholarship from the Grace Baptist Church to D.Y.


References

Allen, J. D. , van Dort, S. C. , Buitelaar, M. , van Tellingen, O. , and Schinkel, A. H. (2003). Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 63, 1339–1344.
PubMed |

Aye, I. L. , Paxton, J. W. , Evseenko, D. A. , and Keelan, J. A. (2007). Expression, localisation and activity of ATP binding cassette (ABC) family of drug transporters in human amnion membranes. Placenta 28, 868–877.
CrossRef | PubMed |

Basso, B. , Giménez, F. , and López, C. (2005). IL-1beta, IL-6 and IL-8 levels in gyneco-obstetric infections. Infect. Dis. Obstet. Gynecol. 13, 207–211.
PubMed |

Bowen, J. M. , Chamley, L. , Keelan, J. A. , and Mitchell, M. D. (2002). Cytokines of the placenta and extra placental membranes: roles and regulation during human pregnancy and parturition. Placenta 23, 257–273.
CrossRef | PubMed |

Braunstein, G. D. , Zeil, F. H. , Allen, A. , Van de Velde, R. , and Wade, M. E. (1976). Prenatal diagnosis of placental steroid sulfatase deficiency. Am. J. Obstet. Gynecol. 126, 716–719.
PubMed |

Ceckova, M. , Libra, A. , Pavek, P. , Nachtigal, P. , Brabec, M. , Fuchs, R. , and Staud, F. (2006). Expression and functional activity of breast cancer resistance protein (BCRP, ABCG2) transporter in the human choriocarcinoma cell line BeWo. Clin. Exp. Pharmacol. Physiol. 33, 58–65.
CrossRef | PubMed |

Dean, M. , Hamon, Y. , and Chimini, G. (2001). The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res. 42, 1007–1017.
PubMed |

Diestra, J. E. , Scheffer, G. L. , Catala, I. , Maliepaard, M. , Schellens, J. H. , Scheper, R. J. , Germa-Lluch, J. R. , and Izquierdo, M. A. (2002). Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. J. Pathol. 198, 213–219.
CrossRef | PubMed |

Doyle, L. A. , Yang, W. , Abruzzo, L. V. , Krogmann, T. , Gao, Y. , Rishi, A. K. , and Ross, D. D. (1998). A multidrug resistant transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA 95, 15 665–15 670.
CrossRef | PubMed |

Ee, P. L. , Kamalakaran, S. , Tonetti, D. , He, X. , Ross, D. D. , and Beck, W. T. (2004). Identification of a novel estrogen response element in the breast cancer resistance protein (ABCG2) gene. Cancer Res. 64, 1247–1251.
CrossRef | PubMed |

Englund, G. , Jacobson, A. , Rorsman, F. , Artursson, P. , Kindmark, A. , and Ronnblom, A. (2007). Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1). Inflamm. Bowel Dis. 13, 291–297.
CrossRef | PubMed |

Evseenko, D. A. , Paxton, J. W. , and Keelan, J. A. (2006). ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R1357–R1365.
PubMed |

Evseenko, D. A. , Paxton, J. W. , and Keelan, J. A. (2007). Independent regulation of apical and basolateral drug transporter expression and function in placental trophoblasts by cytokines, steroids and growth factors. Drug Metab. Dispos. 35, 595–601.
CrossRef | PubMed |

Ifergan, I. , Shafran, A. , Jansen, G. , Hooijberg, J. H. , Scheffer, G. L. , and Assaraf, Y. G. (2004). Folate deprivation results in the loss of breast cancer resistance protein (BCRP/ABCG2) expression. A role for BCRP in cellular folate homeostasis. J. Biol. Chem. 279, 25 527–25 534.
CrossRef | PubMed |

Ifergan, I. , Jansen, G. , and Assaraf, Y. G. (2005). Cytoplasmic confinement of breast cancer resistance protein (BCRP/ABCG2) as a novel mechanism of adaptation to short-term folate deprivation. Mol. Pharmacol. 67, 1349–1359.
CrossRef | PubMed |

Imai, Y. , Tsukahara, S. , Ishikawa, E. , Tsuruo, T. , and Sugimoto, Y. (2002). Estrone and 17beta-estradiol reverse breast cancer resistance protein-mediated multidrug resistance. Jpn. J. Cancer Res. 93, 231–235.
PubMed |

Imai, Y. , Asada, S. , Tsukahara, S. , Ishikawa, E. , Tsuruo, T. , and Sugimoto, Y. (2003). Breast cancer resistance protein exports sulfated estrogens but not free estrogens. Mol. Pharmacol. 64, 610–618.
CrossRef | PubMed |

Johnson, R. F. , Mitchell, C. M. , Giles, W. B. , Bisits, A. , and Zakar, T. (2006). Mechanisms regulating prostaglandin H-2 synthase-2 mRNA levels in amnion and chorion during pregnancy. J. Endocrinol. 188, 603–610.
CrossRef | PubMed |

Jonker, J. W. , Smit, J. W. , Brinkhuis, R. F. , Maliepaard, M. , Beijnen, J. H. , Schellens, J. H. , and Schinkel, A. H. (2000). Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J. Natl Cancer Inst. 92, 1651–1656.
CrossRef | PubMed |

Kalabis, G. M. , Kostaki, A. , Andrews, M. H. , Petropoulos, S. , Gibb, W. , and Matthews, S. G. (2005). Multidrug resistance phosphoglycoprotein (ABCB1) in the mouse placenta: fetal protection. Biol. Reprod. 73, 591–597.
CrossRef | PubMed |

Keelan, J. A. , Blumenstein, M. , Helliwell, R. J. , Sato, T. A. , Marvin, K. W. , and Mitchell, M. D. (2003). Cytokines, prostaglandins and parturition: a review. Placenta 24, S33–S46.
CrossRef | PubMed |

Litman, T. , Jensen, U. , Hansen, A. , Covitz, K. M. , and Zhan, Z. , et al. (2002). Use of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2. Biochim. Biophys. Acta 1565, 6–16.
CrossRef | PubMed |

Madsen, G. , Zakar, T. , Manuelpillai, U. , Wallace, E. , Kwek, K. , Yeo, G. S. H. , Smith, R. , and Mesiano, S. (2004). Intracrine control of estrogen action in human gestational tissues at parturition. J. Soc. Gynecol. Investig. 11, 213–219.
CrossRef | PubMed |

Maliepaard, M. , Scheffer, G. L. , Faneyte, I. F. , van Gastelen, M. A. , Pijnenborg, A. C. , Schinkel, A. H. , van De Vijver, M. J. , Scheper, R. J. , and Schellens, J. H. (2001). Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 61, 3458–3464.
PubMed |

Mathias, A. A. , Hitti, J. , and Unadkat, J. D. (2005). P-Glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R963–R969.
PubMed |

Meyer zu Schwabedissen, H. E. , Grube, M. , Dreisbach, A. , Jedlitschky, G. , Meissner, K. , Linnemann, K. , Fusch, C. , Ritter, C. A. , Volker, U. , and Kroemer, H. K. (2006). Epidermal growth factor-mediated activation of the map kinase cascade results in altered expression and function of ABCG2 (BCRP). Drug Metab. Dispos. 34, 524–533.
CrossRef | PubMed |

Mohrmann, K. , van Eijndhoven, M. A. , Schinkel, A. H. , and Schellens, J. H. (2005). Absence of N-linked glycosylation does not affect plasma membrane localization of breast cancer resistance protein (BCRP/ABCG2). Cancer Chemother. Pharmacol. 56, 344–350.
CrossRef | PubMed |

Ross, D. D. , Karp, J. E. , Chen, T. T. , and Doyle, L. A. (2000). Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood 96, 365–368.
PubMed |

Sadowsky, D. W. , Adams, K. M. , Gravett, M. G. , Witkin, S. S. , and Novy, M. J. (2006). Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am. J. Obstet. Gynecol. 195, 1578–1589.
CrossRef | PubMed |

Sarkadi, B. , Ozvegy-Laczka, C. , Nemet, K. , and Varadi, A. (2004). ABCG2: a transporter for all seasons. FEBS Lett. 567, 116–120.
CrossRef | PubMed |

Schmitz, G. , and Kaminski, W. E. (2001). ABC transporters and cholesterol metabolism. Front. Biosci. 6, D505–D514.
CrossRef | PubMed |

Schmitz, G. , Langmann, T. , and Heimerl, S. (2001). Role of ABCG1 and other ABCG family members in lipid metabolism. J. Lipid Res. 42, 1513–1520.
PubMed |

Staud, F. , and Pavek, P. (2005). Breast cancer resistance protein (BCRP/ABCG2). Int. J. Biochem. Cell Biol. 37, 720–725.
CrossRef | PubMed |

Sun, M. , Kingdom, J. , Baczyk, D. , Lye, S. J. , Matthews, S. G. , and Gibb, W. (2006). Expression of the multidrug resistance P-glycoprotein (ABCB1 glycoprotein) in the human placenta decreases with advancing gestation. Placenta 27, 602–609.
CrossRef | PubMed |

Suzuki, M. , Suzuki, H. , Sugimoto, Y. , and Sugiyama, Y. (2003). ABCG2 transports sulfated conjugates of steroids and xenobiotics. J. Biol. Chem. 278, 22 644–22 649.
CrossRef | PubMed |

Takada, T. , Suzuki, H. , Gotoh, Y. , and Sugiyama, Y. (2005a). Regulation of the cell surface expression of human BCRP/ABCG2 by the phosphorylation state of Akt in polarized cells. Drug Metab. Dispos. 33, 905–909.
CrossRef | PubMed |

Takada, T. , Suzuki, H. , and Sugiyama, Y. (2005b). Characterization of polarized expression of point- or deletion-mutated human BCRP/ABCG2 in LLC-PK1 cells. Pharm. Res. 22, 458–464.
CrossRef | PubMed |

Volk, E. L. , Farley, K. M. , Wu, Y. , Li, F. , Robey, R. W. , and Schneider, E. (2002). Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance. Cancer Res. 62, 5035–5040.
PubMed |

Wang, H. , Zhou, L. , Gupta, A. , Vethanayagam, R. R. , Zhang, Y. , Unadkat, J. D. , and Mao, Q. (2006). Regulation of BCRP/ABCG2 expression by progesterone and 17beta-estradiol in human placental BeWo cells. Am. J. Physiol. Endocrinol. Metab. 290, E798–E807.
CrossRef | PubMed |

Yeboah, D. , Sun, M. , Kingdom, J. , Baczyk, D. , Lye, S. J. , Matthews, S. G. , and Gibb, W. (2006). Expression of breast cancer resistance protein (BCRP/ABCG2) in human placenta throughout gestation and at term before and after labor. Can. J. Physiol. Pharmacol. 84, 1251–1258.
CrossRef | PubMed |

Young, A. M. , Allen, C. E. , and Audus, K. L. (2003). Efflux transporters of the human placenta. Adv. Drug Deliv. Rev. 55, 125–132.
CrossRef | PubMed |



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