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¹ Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, Minnesota and ² Drug Discovery Biosciences Division, SRI International, Menlo Park, California

Requests for reprints: Kalpna Gupta, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Mayo Mail Code 480, 420 Delaware Street Southeast, Minneapolis, MN 55455. Phone: 612-625-7648; Fax: 612-625-6919. E-mail: gupta014{at}umn.edu

Estrogen promotes the growth of breast cancer via estrogen receptors (ER). Earlier studies showed that the opioid receptor antagonist naloxone inhibits MCF-7 breast cancer growth in mice. We examined the cellular and molecular mechanism of naloxone antagonism of ER activity in human MCF-7 cells. Naloxone (100 nmol/L) inhibited 17ß-estradiol (E2)–induced (10 nmol/L) MCF-7 cell proliferation by 65% and mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation. Naloxone blocked the E2-induced activation of ER, with 85% inhibition after 5 minutes and 100% recovery after 60 minutes. This assay is based on quantitation of E2-activated nuclear ER binding to the immobilized coactivator peptide. A significant decrease in E2-induced ER transactivation was observed in the presence of naloxone in the estrogen response element-luciferase reporter assay (P < 0.05, E2 versus E2 + naloxone). Naloxone also blocked E2-induced down-regulation of ER mRNA at 30 minutes and 6 hours. Although naloxone inhibits ER activity directly, it also induces a cross-talk between µ-opioid receptor (MOR) and ER. Immunoprecipitates with anti-MOR antibody showed the presence of ER in cells incubated with E2 in the presence of naloxone but not in cells incubated with E2 or naloxone alone. Higher amounts of ER associated with MOR after 60 minutes compared with 10 minutes of incubation. Naloxone inhibited E2-bovine serum albumin-FITC binding to plasma membrane–associated ER and also inhibited the direct binding of [³H]E2 to ER. Thus, naloxone modulates ER activity directly as well as indirectly via MOR. This study suggests that naloxone-like compounds can be developed as novel therapeutic molecules for breast cancer therapy. [Mol Cancer Ther 2006;5(3):611–20]

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Received 1/12/05; revised 12/14/05; accepted 1/11/06.

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