title: The neuropeptide y y(1) receptor: a diagnostic marker? Expression in mcf-7 breast cancer cells is down-regulated by antiestrogens in vitro and in xenografts.
abstract: The neuropeptide Y (NPY) Y(1) receptor (Y(1)R) has been suggested as a tumor marker for in vivo imaging and as a therapeutic target. In view of the assumed link between estrogen receptor (ER) and Y(1)R in mammary carcinoma and with respect to the development of new diagnostic tools, we investigated the Y(1)R protein expression in human MCF-7 cell variants differing in ER content and sensitivity against antiestrogens. ER and Y(1)R expression were quantified by radioligand binding using [(3)H]-17β-estradiol and the Y(1)R selective antagonist [(3)H]-UR-MK114, respectively. The latter was used for cellular binding studies and for autoradiography of MCF-7 xenografts. The fluorescent ligands Cy5-pNPY (universal Y(1)R, Y(2)R and Y(5)R agonist) and UR-MK22 (selective Y(1)R antagonist), as well as the selective antagonists BIBP3226 (Y(1)R), BIIE0246 (Y(2)R) and CGP71683 (Y(5)R) were used to identify the NPY receptor subtype(s) by confocal microscopy. Y(1)R functionality was determined by mobilization of intracellular Ca(2+). Sensitivity of MCF-7 cells against antiestrogen 4-hydroxytamoxifen correlated directly with the ER content. The exclusive expression of Y(1)Rs was confirmed by confocal microscopy. The Y(1)R protein was up-regulated (100%) by 17β-estradiol (EC(50) 20 pM) and the predominant role of ERα was demonstrated by using the ERα-selective agonist "propylpyrazole triol". 17β-Estradiol-induced over-expression of functional Y(1)R protein was reverted by the antiestrogen fulvestrant (IC(50) 5 nM) in vitro. Furthermore, tamoxifen treatment of nude mice resulted in an almost total loss of Y(1)Rs in MCF-7 xenografts. In conclusion, the value of the Y(1)R as a target for therapy and imaging in breast cancer patients may be compromised due to Y(1)R down-regulation induced by hormonal (antiestrogen) treatment.
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Memminger
authors.forename: Max
authors.initials: M
authors.lastname: Keller
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Lopuch
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pop
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Erwin
authors.initials: E
authors.lastname: von Angerer
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D020847:Estrogen Receptor Modulators; C534492:Nalpha-(2,2-diphenylacetyl)-N-(4-hydroxybenzyl)-Nomega-propanoylargininamide; D009478:Neuropeptide Y; D011960:Receptors, Estrogen; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D001120:Arginine; D002118:Calcium