Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness

Youyi Chen, I. Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I. Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Sou, Junichiro Futami, Miyoko Kubo, Endy Widya PutrantoTakashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)627-640
Number of pages14
JournalNeoplasia (United States)
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 1 2019

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CD146 Antigens
Epithelial-Mesenchymal Transition
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Growth
Cell Surface Receptors
Disease Progression
Transcription Factors
Up-Regulation
Down-Regulation
Cytokines
Inflammation
Phenotype
Lung
Survival

ASJC Scopus subject areas

  • Cancer Research

Cite this

Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. / Chen, Youyi; Sumardika, I. Wayan; Tomonobu, Nahoko; Kinoshita, Rie; Inoue, Yusuke; Iioka, Hidekazu; Mitsui, Yosuke; Saito, Ken; Ruma, I. Made Winarsa; Sato, Hiroki; Yamauchi, Akira; Murata, Hitoshi; Yamamoto, Ken-ichi; Tomida, Shuta; Shien, Kazuhiko; Yamamoto, Hiromasa; Sou, Junichi; Futami, Junichiro; Kubo, Miyoko; Putranto, Endy Widya; Murakami, Takashi; Liu, Ming; Hibino, Toshihiko; Nishibori, Masahiro; Kondo, Eisaku; Toyooka, Shinichi; Sakaguchi, Masakiyo.

In: Neoplasia (United States), Vol. 21, No. 7, 01.07.2019, p. 627-640.

Research output: Contribution to journalArticle

Chen, Y, Sumardika, IW, Tomonobu, N, Kinoshita, R, Inoue, Y, Iioka, H, Mitsui, Y, Saito, K, Ruma, IMW, Sato, H, Yamauchi, A, Murata, H, Yamamoto, K, Tomida, S, Shien, K, Yamamoto, H, Sou, J, Futami, J, Kubo, M, Putranto, EW, Murakami, T, Liu, M, Hibino, T, Nishibori, M, Kondo, E, Toyooka, S & Sakaguchi, M 2019, 'Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness', Neoplasia (United States), vol. 21, no. 7, pp. 627-640. https://doi.org/10.1016/j.neo.2019.04.006
Chen, Youyi ; Sumardika, I. Wayan ; Tomonobu, Nahoko ; Kinoshita, Rie ; Inoue, Yusuke ; Iioka, Hidekazu ; Mitsui, Yosuke ; Saito, Ken ; Ruma, I. Made Winarsa ; Sato, Hiroki ; Yamauchi, Akira ; Murata, Hitoshi ; Yamamoto, Ken-ichi ; Tomida, Shuta ; Shien, Kazuhiko ; Yamamoto, Hiromasa ; Sou, Junichi ; Futami, Junichiro ; Kubo, Miyoko ; Putranto, Endy Widya ; Murakami, Takashi ; Liu, Ming ; Hibino, Toshihiko ; Nishibori, Masahiro ; Kondo, Eisaku ; Toyooka, Shinichi ; Sakaguchi, Masakiyo. / Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. In: Neoplasia (United States). 2019 ; Vol. 21, No. 7. pp. 627-640.
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AU - Kinoshita, Rie

AU - Inoue, Yusuke

AU - Iioka, Hidekazu

AU - Mitsui, Yosuke

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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

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