MAPK kinase 3 is a tumor suppressor with reduced copy number in breast cancer.
Cancers are initiated as a result of changes that occur in the genome. Identification of gains and losses in the structure and expression of tumor-suppressor genes and oncogenes lies at the root of the understanding of cancer cell biology. Here, we show that the mitogen-activated protein kinase (MAPK) MKK3 suppresses the growth of breast cancer, in which it varies in copy number. A pervasive loss of MKK3 gene copy number in patients with breast cancer is associated with an impairment of MKK3 expression and protein level in malignant tissues. To assess the functional role of MKK3 in breast cancer, we showed in an animal model that MKK3 activity is required for suppression of tumor growth. Active MKK3 enhanced expression of the cyclin-dependent kinase inhibitors p21(Cip1/Waf1) and p27(Kip1), leading to increased cell-cycle arrest in G1 phase of the cell cycle. Our results reveal the functional significance of MKK3 as a tumor suppressor and improve understanding of the dynamic role of the MAPK pathway in tumor progression.
Authors' Affiliations: Departments of Microbiology and Immunology, Pediatrics, Physiology and Biophysics, and Pathology, Dalhousie University; Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada; Department of Medical Oncology, General Hospital of the People's Liberation Army, Beijing; and Institute of Zoonosis, College of Animal Sciences and Veterinary Medicine, Jilin University, Changchun, Jilin, China.
Adam J
AJ
MacNeil
Shun-Chang
SC
Jiao
Lori A
LA
McEachern
Yong Jun
YJ
Yang
Amanda
A
Dennis
Haiming
H
Yu
Zhaolin
Z
Xu
Jean S
JS
Marshall
Tong-Jun
TJ
Lin
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D048371:MAP Kinase Kinase 3 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse