Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer.
Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.
Department of Translational Molecular Pathology.
Warapen
W
Treekitkarnmongkol
Department of Translational Molecular Pathology.|Present address: Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan and.
Hiroshi
H
Katayama
Department of Translational Molecular Pathology.
Kazuharu
K
Kai
Department of Translational Molecular Pathology.|Present address: Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan and.
Kaori
K
Sasai
Department of Translational Molecular Pathology.|Genomics Field Application, Agilent Technologies, Santa Clara, CA 95051, USA.
Jennifer Carter
JC
Jones
Department of Bioinformatics and Computational Biology.
Jing
J
Wang
Department of Bioinformatics and Computational Biology.
Li
L
Shen
Department of Pathology.
Aysegul A
AA
Sahin
Department of Veterinary Medicine and Surgery.
Mihai
M
Gagea
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and.
Naoto T
NT
Ueno
Department of Bioinformatics and Computational Biology.|Department of Medicine, Dan L Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA.
Chad J
CJ
Creighton
Department of Translational Molecular Pathology, ssen@mdanderson.org.
Subrata
S
Sen
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D064096:Aurora Kinase A / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011247:Pregnancy
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D064096:Aurora Kinase A