Amplification and over‐expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells. Issue 1 (January 2014)

• Record Type: Journal Article
• Authors: Fan, Yihui; Ge, Ningling; Wang, Xiaosong; Sun, Wenjing; Mao, Renfang; Bu, Wen; Creighton, Chad J; Zheng, Pingju; Vasudevan, Sanjeev; An, Lei; Yang, Jinshu; Zhao, Yi‐Jue; Zhang, Huiyuan; Li, Xiao‐Nan; Rao, Pulivarthi H; Leung, Eastwood; Lu, Yong‐Jie; Gray, Joe W; Schiff, Rachel; Hilsenbeck, Susan G; Osborne, C Kent; Yang, Jianhua; Zhang, Hong
• Is Part Of: Journal of pathology. Volume 232:Issue 1(2014)
• Page Start: 75
• Page End: 86
• Publication Date: 2014-01
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4283
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4283-abs-0001"> <title>Abstract</title> <p id="path4283-para-0001"> <bold>Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the <italic>MAP3K</italic>3 gene as a potential therapeutic target in breast cancer. This gene encodes mitogen‐activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), which has not yet been reported to be associated with cancer‐causing genetic aberrations. We found that <italic>MAP3K3</italic> was amplified in approximately 8–20% of breast cancers. Knockdown of <italic>MAP3K3</italic> expression significantly inhibited cell proliferation and colony formation in <italic>MAP3K3</italic>‐amplified breast cancer cell lines MCF‐7 and MDA‐MB‐361 but not in <italic>MAP3K3</italic> non‐amplified breast cancer cells. Knockdown of <italic>MAP3K3</italic> expression in <italic>MAP3K3</italic>‐amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNF<italic>α</italic> and TRAIL, as well as doxorubicin, VP‐16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of <italic>MAP3K3</italic>, in collaboration with <italic>Ras</italic>, induced colony formation in both primary mouse embryonic fibroblasts and immortalized human breast epithelial cells (MCF‐10A). Combined, these results suggest that MAP3K3 contributes to breast carcinogenesis and may endow resistance of breast cancer cells to cytotoxic chemotherapy. Therefore, MAP3K3 may be a valuable therapeutic target in patients with <italic>MAP3K3</italic>‐amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize <italic>MAP3K3</italic>‐amplified breast cancer cells to chemotherapy. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</bold> </p> </abstract>