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¹ Vectorologie et Transfert de Gènes, CNRS UMR 8121, Institut Gustave Roussy, 94805 Villejuif Cedex, France
² Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hopitaux de Paris, Hôpital Bicêtre, 75 rue du General Leclerc, 94270 Le Kremlin Bicêtre, France
³ Biochimie Médicale et Biologie Moléculaire, CNRS UMR 6198, Faculté de Médecine, 51095 Reims Cedex, France
⁴ Laboratoire d’Oncogénétique, INSERM U735, Centre René Huguenin, 92210 St-Cloud, France
⁵ INSERM U690, Hôpital Robert Debré, 48 Boulevard Serurier, 75019 Paris, France
⁶ INSERM U844, 34090 Montpellier, France
⁷ Service d’Endocrinologie et Médecine de la Reproduction, Hôpital Pitié Salpêtrière, 47-83, boulevard de l’Hôpital, 75651 Paris Cedex 13, France
⁸ Faculté de Médecine Paris Sud, Université Paris XI, 94275 Le Kremlin Bicêtre, France

(Correspondence should be addressed to N de Roux; Email: deroux{at}rdebre.inserm.fr)

KiSS1 is a putative metastasis suppressor gene in melanoma and breast cancer-encoding kisspeptins, which are also described as neuroendocrine regulators of the gonadotropic axis. Negative as well as positive regulation of KiSS1 gene expression by estradiol (E₂) has been reported in the hypothalamus. Estrogen receptor (ER level is recognized as a marker of breast cancer, raising the question of whether expression of KiSS1 and its G-protein-coupled receptor (GPR54) is down- or upregulated by estrogens in breast cancer cells. KiSS1 was found to be expressed in MDA-MB-231, MCF7, and T47D cell lines, but not in ZR75-1, L56Br, and MDA-MB-435 cells. KiSS1 mRNA levels decreased significantly in ER-negative MDA-MB-231 cells expressing recombinant ER. In contrast, tamoxifen (TAM) treatment of ER-positive MCF7 and T47D cells increased KiSS1 and GPR54 levels. The clinical relevance of this negative regulation of KiSS1 and GPR54 by E₂ was then studied in postmenopausal breast cancers. KiSS1 mRNA increased with the grade of the breast tumors. ER-positive invasive primary tumors expressed sevenfold lower KiSS1 levels than ER-negative tumors. Among ER-positive breast tumors from postmenopausal women treated with TAM, high KiSS1 combined with high GPR54 mRNA tumoral levels was unexpectedly associated with shorter relapse-free survival (RFS) relative to tumors expressing low tumoral mRNA levels of both genes. The contradictory observation of putative metastasis inhibitor role of kisspeptins and RFS to TAM treatment suggests that evaluation of KiSS1 and its receptor tumoral mRNA levels could be new interesting markers of the tumoral resistance to anti-estrogen treatment.