TY - JOUR
T1 - Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness
AU - Chen, Youyi
AU - Sumardika, I. Wayan
AU - Tomonobu, Nahoko
AU - Kinoshita, Rie
AU - Inoue, Yusuke
AU - Iioka, Hidekazu
AU - Mitsui, Yosuke
AU - Saito, Ken
AU - Ruma, I. Made Winarsa
AU - Sato, Hiroki
AU - Yamauchi, Akira
AU - Murata, Hitoshi
AU - Yamamoto, Ken ichi
AU - Tomida, Shuta
AU - Shien, Kazuhiko
AU - Yamamoto, Hiromasa
AU - Sou, Junichi
AU - Futami, Junichiro
AU - Kubo, Miyoko
AU - Putranto, Endy Widya
AU - Murakami, Takashi
AU - Liu, Ming
AU - Hibino, Toshihiko
AU - Nishibori, Masahiro
AU - Kondo, Eisaku
AU - Toyooka, Shinichi
AU - Sakaguchi, Masakiyo
N1 - Funding Information:
This research was supported in part by JSPS KAKENHI Grant Number 17H03577 to M.S., and by funds to M.S. from the Smoking Research Foundation, the Terumo Life Science Foundation, and the Takeda Science Foundation.
Publisher Copyright:
© 2019 The Authors
PY - 2019/7
Y1 - 2019/7
N2 - Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s)of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT)in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.
AB - Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s)of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT)in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.
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U2 - 10.1016/j.neo.2019.04.006
DO - 10.1016/j.neo.2019.04.006
M3 - Article
C2 - 31100639
AN - SCOPUS:85065519782
VL - 21
SP - 627
EP - 640
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 7
ER -