Altered microRNA Expression Profiles and Regulation of INK4A/CDKN2A Tumor Suppressor Genes in Canine Breast Cancer Models

• Published in: Journal of cellular biochemistry 2015-12, Vol.116 (12), p.2956-2969
• Main Authors: Lutful Kabir, Farruk Mohammad, DeInnocentes, Patricia, Bird, Richard Curtis
• Format: Article
• Language: English
• Subjects: Animals; BREAST CANCER; Breast Neoplasms - genetics; Breast Neoplasms - pathology; CANINE CANCER MODEL; Cell Line, Tumor; CYCLIN-DEPENDENT KINASE INHIBITOR; Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Disease Models, Animal; Dogs; Female; Gene Expression Regulation, Neoplastic; Humans; INK4A; MicroRNAs - biosynthesis; miRNA; Molecular Targeted Therapy; Transcriptome; TUMOR SUPPRESSOR
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.25243

ABSTRACT microRNA (miRNA) expression profiling of cancer versus normal cells may reveal the characteristic regulatory features that can be correlated to altered gene expression in both human and animal models of cancers. In this study, the comprehensive expression profiles of the 277 highly characterized miRNAs from the canine genome were evaluated in spontaneous canine mammary tumor (CMT) models harboring defects in a group of cell cycle regulatory and potent tumor suppressor genes of INK4/CDKN2 family including p16/INK4A, p14ARF, and p15/INK4B. A large number of differentially expressed miRNAs were identified in three CMT cell lines to potentially target oncogenes, tumor suppressor genes and cancer biomarkers. A group of the altered miRNAs were identified by miRNA target prediction tools for regulation of the INK4/CDKN2 family tumor suppressor genes. miRNA‐141 was experimentally validated for INK4A 3′‐UTR target binding in the CMT cell lines providing an essential mechanism for the post‐transcriptional regulation of the INK4A tumor suppressor gene in CMT models. A well‐recognized group of miRNAs including miR‐21, miR‐155, miR‐9, miR‐34a, miR‐143/145, and miR‐31 were found to be altered in both CMTs and human breast cancer. These altered miRNAs might serve as potential targets for advancing the development of future therapeutic reagents. These findings further strengthen the validity and use of canine breast cancers as appropriate models for the study of human breast cancers. J. Cell. Biochem. 116: 2956–2969, 2015. © 2015 Wiley Periodicals, Inc.