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 language | English |
|---|---|
| Pages (from-to) | 627-640 |
| Number of pages | 14 |
| Journal | Neoplasia (United States) |
| Volume | 21 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 1 2019 |
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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 journal › Article
}
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
PY - 2019/7/1
Y1 - 2019/7/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85065519782&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065519782&partnerID=8YFLogxK
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 -