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¹ Université de Lyon, Lyon1, ISPB, Lyon F-69008, France² Inserm, U590, Lyon F-69008, France³ Centre Léon Bérard, FNCLCC, Lyon F-69008, France⁴ Laboratoire de Toxicologie, Faculté de Pharmacie, Université de Lyon, Lyon F-69008, France⁵ Laboratoire de Ciblage Thérapeutique en Cancérologie, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre Bénite F-69495, France⁶ Centre René Huguenin, FNCLCC, St-Cloud F-92210, France⁷ Inserm, U735, St-Cloud F-92210, France⁸ University of Illinois at Chicago Cancer Center, 239 Medical Center Administration Building (MC700), 914 South Wood Street, Chicago, Illinois 60612, USA

(Correspondence should be addressed to L Payen, INSERM U590, Laboratoire de Cytologie Analytique, Institut des Sciences Biologiques et Pharmaceutiques (ISPB) 8, Avenue Rockefeller, 69008 Lyon, France; Email: lea.payen{at}recherche.univ-lyon1.fr)

ABCC11 (Multidrug resistance protein 8; MRP8), a plasma membrane ATP-binding cassette transporter, has been implicated in drug resistance of breast cancer by virtue of its ability to confer resistance to fluoropyrimidines and to efflux methotrexate, and by its expression in this tumor. Expression of ABCC11 in breast, a hormonally regulated tissue, as well as the pump's ability to transport estrogen conjugates, suggest the possibility that expression of ABCC11 may be susceptible to regulation by estrogen. However, nothing is currently known about regulation of this gene. In this study, estradiol (E₂) treatment reduced expression of ABCC11 mRNA in estrogen receptor (ER)--positive MCF7 cells, and E₂ antagonists such as ICI 182 780 and tamoxifen (TAM) abrogated E₂-mediated downregulation. ABCC11 expression was positively correlated with ER- expression in both breast cell lines, and two independent series of tumors from postmenopausal patients. In addition, expression of ABCC11 was upregulated in MCF7 cells exposed to TAM for 72 h, and was overexpressed in TAM-resistant cell lines. Drug sensitivity analysis of the TAM-resistant cells indicated that they were also resistant to 5-fluorouracil (5-FU), consistent with the reported ability of ABCC11 to confer resistance to this agent. These studies indicate that ABCC11 expression is negatively regulated by E₂, but that ABCC11 expression is high in high-expressing ER- breast cancers. Our findings support the notion that expression of ABCC11 in ER--positive breast cancers may contribute to decreased sensitivity to chemotherapy combinations that include 5-FU. ABCC11 may be a potential predictive tool in the choice of anticancer therapies in ER-positive breast cancers resistant to TAM.