Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells

Hong Zhang, Yihui Fan, Ningling Ge, Xiaosong Wang, Wenjing Sun, Renfang Mao, Wen Bu, Chad J. Creighton, Pingju Zheng, Sanjeev Vasudevan, Lei An, Jinshu Yang, Yi Jue Zhao, Huiyuan Zhang, Xiao Nan Li, Pulivarthi H. Rao, Eastwood Leung, Yong Jie Lu, Joe Gray, Rachel Schiff & 3 others Susan G. Hilsenbeck, C. Kent Osborne, Jianhua Yang

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the MAP3K3 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 MAP3K3 was amplified in approximately 8-20% of breast cancers. Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3-amplified breast cancer cell lines MCF-7 and MDA-MB-361 but not in MAP3K3 non-amplified breast cancer cells. Knockdown of MAP3K3 expression in MAP3K3-amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNFα and TRAIL, as well as doxorubicin, VP-16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of MAP3K3, in collaboration with Ras, 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 MAP3K3-amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3-amplified breast cancer cells to chemotherapy.

Original languageEnglish (US)
Pages (from-to)75-86
Number of pages12
JournalJournal of Pathology
Volume232
Issue number1
DOIs
StatePublished - Jan 2014

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Breast Neoplasms
Gene Expression
Survival
MAP Kinase Kinase Kinase 3
Breast
Drug Therapy
Gene Amplification
Etoposide
Computational Biology
Fluorouracil
Doxorubicin
Genes
Carcinogenesis
Phosphotransferases
Fibroblasts
Epithelial Cells
Cell Proliferation
Cell Line
Therapeutics
Pharmaceutical Preparations

Keywords

  • breast cancer
  • chemo-resistance
  • MAP3K3
  • oncogene

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells. / Zhang, Hong; 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; Schiff, Rachel; Hilsenbeck, Susan G.; Osborne, C. Kent; Yang, Jianhua.

In: Journal of Pathology, Vol. 232, No. 1, 01.2014, p. 75-86.

Research output: Contribution to journalArticle

Zhang, H, Fan, Y, Ge, N, Wang, X, Sun, W, Mao, R, Bu, W, Creighton, CJ, Zheng, P, Vasudevan, S, An, L, Yang, J, Zhao, YJ, Zhang, H, Li, XN, Rao, PH, Leung, E, Lu, YJ, Gray, J, Schiff, R, Hilsenbeck, SG, Osborne, CK & Yang, J 2014, 'Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells', Journal of Pathology, vol. 232, no. 1, pp. 75-86. https://doi.org/10.1002/path.4283
Zhang, Hong ; 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 ; Schiff, Rachel ; Hilsenbeck, Susan G. ; Osborne, C. Kent ; Yang, Jianhua. / Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells. In: Journal of Pathology. 2014 ; Vol. 232, No. 1. pp. 75-86.
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abstract = "Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the MAP3K3 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 MAP3K3 was amplified in approximately 8-20{\%} of breast cancers. Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3-amplified breast cancer cell lines MCF-7 and MDA-MB-361 but not in MAP3K3 non-amplified breast cancer cells. Knockdown of MAP3K3 expression in MAP3K3-amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNFα and TRAIL, as well as doxorubicin, VP-16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of MAP3K3, in collaboration with Ras, 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 MAP3K3-amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3-amplified breast cancer cells to chemotherapy.",
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AU - Zhang, Hong

AU - Fan, Yihui

AU - Ge, Ningling

AU - Wang, Xiaosong

AU - Sun, Wenjing

AU - Mao, Renfang

AU - Bu, Wen

AU - Creighton, Chad J.

AU - Zheng, Pingju

AU - Vasudevan, Sanjeev

AU - An, Lei

AU - Yang, Jinshu

AU - Zhao, Yi Jue

AU - Zhang, Huiyuan

AU - Li, Xiao Nan

AU - Rao, Pulivarthi H.

AU - Leung, Eastwood

AU - Lu, Yong Jie

AU - Gray, Joe

AU - Schiff, Rachel

AU - Hilsenbeck, Susan G.

AU - Osborne, C. Kent

AU - Yang, Jianhua

PY - 2014/1

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N2 - Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the MAP3K3 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 MAP3K3 was amplified in approximately 8-20% of breast cancers. Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3-amplified breast cancer cell lines MCF-7 and MDA-MB-361 but not in MAP3K3 non-amplified breast cancer cells. Knockdown of MAP3K3 expression in MAP3K3-amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNFα and TRAIL, as well as doxorubicin, VP-16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of MAP3K3, in collaboration with Ras, 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 MAP3K3-amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3-amplified breast cancer cells to chemotherapy.

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