title: Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape.
abstract: Oncogenic-stress-induced senescence (OIS) is a stress response allowing normal cells, when receiving oncogenic signals, to stably arrest their proliferation. OIS thus acts to prevent aberrant cell proliferation and tumor formation. To identify novel tumor suppressive pathways, we have recently completed a loss-of-function genetic screen to identify novel genes promoting escape from OIS and thus, potentially, tumor formation when their functions are lost. Using this approach, we unexpectedly found that loss of function of the multidrug resistance protein 3 (MRP3 or ABCC3) promotes escape from OIS in human epithelial cells. Importantly, ABCC3 expression is reduced in human skin tumors, and ABCC3-knockout mice display increased sensitivity to RAS-induced skin carcinogenesis, concomitantly with decreased OIS. ABCC3 participates in resistance to chemotherapy via its transporter activity. Our data show that this transporter activity is involved in ABCC3-induced senescence, demonstrating that this protein has a complex role in cancer, since its loss of function may promote escape from OIS and tumor formation whereas its gain of function promotes resistance to chemotherapy.
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Wiel
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: B
authors.initials: B
authors.lastname: Gras
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Vindrieux
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Warnier
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Gitenay
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: B
authors.initials: B
authors.lastname: Le Calvé
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Ferrand
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Augert
authors.affiliation: Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|CNRS UMR5286, Lyon, France.|Centre Léon Bérard, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Bernard
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D051379:Mice; D009369:Neoplasms / Q000503:physiopathology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; C095122:multidrug resistance protein 3