Tropomodulin 1 expression driven by NF-κB enhances breast cancer growth.
Triple-negative breast cancers (TNBC), which include the basal-like and claudin-low disease subtypes, are aggressive malignancies for which effective therapeutic targets are lacking. NF-κB activation has an established role in breast malignancy, and it is higher in TNBC than other breast cancer subtypes. On this basis, we hypothesized that proteins derived from NF-κB target genes might be molecular targets for TNBC therapy. In this study, we conducted a microarray-based screen for novel NF-κB-inducible proteins as candidate therapeutic targets, identifying tropomodulin 1 (TMOD1) as a lead candidate. TMOD1 expression was regulated directly by NF-κB and was significantly higher in TNBC than other breast cancer subtypes. TMOD1 elevation is associated with enhanced tumor growth in a mouse tumor xenograft model and in a 3D type I collagen culture. TMOD1-dependent tumor growth was correlated with MMP13 induction, which was mediated by TMOD1-dependent accumulation of β-catenin. Overall, our study highlighted a novel TMOD1-mediated link between NF-κB activation and MMP13 induction, which accounts in part for the NF-κB-dependent malignant phenotype of TNBC.
Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Cell Signal Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.
Taku
T
Ito-Kureha
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Naohiko
N
Koshikawa
Department of Life Science and Medical Bio-science, Waseda University, Tokyo, Japan.
Mizuki
M
Yamamoto
Department of Life Science and Medical Bio-science, Waseda University, Tokyo, Japan.
Kentaro
K
Semba
Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Noritaka
N
Yamaguchi
Cell Signal Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.
Tadashi
T
Yamamoto
Graduate School of Medicine, Kochi University, Kochi, Japan.
Motoharu
M
Seiki
Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. jun-i@ims.u-tokyo.ac.jp.
Jun-Ichiro
J
Inoue
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051348:Tropomodulin / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D016328:NF-kappa B; C495829:TMOD1 protein, human; D051348:Tropomodulin