TY - JOUR
T1 - The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis
AU - Takeuchi, Yasuto
AU - Kimura, Natsuko
AU - Murayama, Takahiko
AU - Machida, Yukino
AU - Iejima, Daisuke
AU - Nishimura, Tatsunori
AU - Terashima, Minoru
AU - Wang, Yuming
AU - Li, Mengjiao
AU - Sakamoto, Reiko
AU - Yamamoto, Mizuki
AU - Itano, Naoki
AU - Inoue, Yusuke
AU - Ito, Masataka
AU - Yoshida, Nobuaki
AU - Inoue, Jun Ichiro
AU - Akashi, Koichi
AU - Saya, Hideyuki
AU - Fujita, Koji
AU - Kuroda, Masahiko
AU - Kitabayashi, Issay
AU - Voon, Dominic
AU - Suzuki, Takeshi
AU - Tojo, Arinobu
AU - Gotoh, Noriko
N1 - Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/10/26
Y1 - 2021/10/26
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Cancer-associated fibroblasts
KW - FRS3
KW - NF-κB
KW - Premalignant inflammation
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U2 - 10.1073/pnas.2103658118
DO - 10.1073/pnas.2103658118
M3 - Article
C2 - 34663724
AN - SCOPUS:85117388080
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
M1 - e2103658118
ER -