title: miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy.
abstract: The female mammary gland is a very dynamic organ that undergoes continuous tissue remodeling during adulthood. Although it is well established that the number of menstrual cycles and pregnancy (in this case transiently) increase the risk of breast cancer, the reasons are unclear. Growing clinical and experimental evidence indicates that improper involution plays a role in the development of this malignancy. Recently, we described the miR-424(322)/503 cluster as an important regulator of mammary epithelial involution after pregnancy. Here, through the analysis of ∼3000 primary tumors, we show that miR-424(322)/503 is commonly lost in a subset of aggressive breast cancers and describe the genetic aberrations that inactivate its expression. Furthermore, through the use of a knockout mouse model, we demonstrate for the first time that loss of miR-424(322)/503 promotes breast tumorigenesis in vivo. Remarkably, we found that loss of miR-424(322)/503 promotes chemoresistance due to the up-regulation of two of its targets: BCL-2 and insulin-like growth factor-1 receptor (IGF1R). Importantly, targeted therapies blocking the aberrant activity of these targets restore sensitivity to chemotherapy. Overall, our studies reveal miR-424(322)/503 as a tumor suppressor in breast cancer and provide a link between mammary epithelial involution, tumorigenesis, and the phenomenon of chemoresistance.
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne NE1 3BZ, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodriguez-Barrueco
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Nekritz
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille 13009, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: St. Jude Children's Research Hospital, Kay Research and Care Center, IA6053, Memphis, Tennessee 38105, USA.
authors.forename: Jiyang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Systems Biology, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Sanchez-Garcia
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Tizita Z
authors.initials: TZ
authors.lastname: Zeleke
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Gorbatenko
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille 13009, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Department of Cell, Developmental, and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ezhkova
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille 13009, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne NE1 3BZ, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Llobet-Navas
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics; D020687:cdc25 Phosphatases / Q000235:genetics
chemical_list: C000597236:IGF1R protein, human; C583176:MIRN424 microRNA, mouse; C554214:MIRN424 microrna, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; C556275:Mirn503 microRNA, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1; D020687:cdc25 Phosphatases
keywords: breast cancer; chemoresistance; microRNA; tumor suppressor