The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis

Yasuto Takeuchi, Natsuko Kimura, Takahiko Murayama, Yukino Machida, Daisuke Iejima, Tatsunori Nishimura, Minoru Terashima, Yuming Wang, Mengjiao Li, Reiko Sakamoto, Mizuki Yamamoto, Naoki Itano, Yusuke Inoue, Masataka Ito, Nobuaki Yoshida, Jun Ichiro Inoue, Koichi Akashi, Hideyuki Saya, Koji Fujita, Masahiko KurodaIssay Kitabayashi, Dominic Voon, Takeshi Suzuki, Arinobu Tojo, Noriko Gotoh

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2β, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β deficiency in mouse mammary tumor virus (MMTV)–ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found that colocalization of FRS2β and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor–κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB–induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β–NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.

Original languageEnglish
Article numbere2103658118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number43
DOIs
Publication statusPublished - Oct 26 2021

All Science Journal Classification (ASJC) codes

  • General

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