title: Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells.
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.
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Ningling
authors.initials: N
authors.lastname: Ge
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.forename: Renfang
authors.initials: R
authors.lastname: Mao
authors.forename: Wen
authors.initials: W
authors.lastname: Bu
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Pingju
authors.initials: P
authors.lastname: Zheng
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Vasudevan
authors.forename: Lei
authors.initials: L
authors.lastname: An
authors.forename: Jinshu
authors.initials: J
authors.lastname: Yang
authors.forename: Yi-Jue
authors.initials: YJ
authors.lastname: Zhao
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.forename: Pulivarthi H
authors.initials: PH
authors.lastname: Rao
authors.forename: Eastwood
authors.initials: E
authors.lastname: Leung
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Lu
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D019295:Computational Biology; D004317:Doxorubicin / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005472:Fluorouracil / Q000494:pharmacology; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D004317:Doxorubicin; D048748:MAP Kinase Kinase Kinase 3; C482625:MAP3K3 protein, human; D005472:Fluorouracil
keywords: MAP3K3; breast cancer; chemo-resistance; oncogene