PMID- 34663724 OWN - NLM STAT- MEDLINE DCOM- 20211210 LR - 20211214 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 43 DP - 2021 Oct 26 TI - The membrane-linked adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis. LID - 10.1073/pnas.2103658118 [doi] LID - e2103658118 AB - Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2beta, 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. FRS2beta 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 FRS2beta-deficient premalignant tissues. We found that colocalization of FRS2beta and the NEMO subunit of the IkappaB kinase complex in early endosomes led to activation of nuclear factor-kappaB (NF-kappaB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-kappaB-induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2beta contain more stroma. The elucidation of the FRS2beta-NF-kappaB axis uncovers a molecular link between the proinflammatory changes and the disease onset. CI - Copyright (c) 2021 the Author(s). Published by PNAS. FAU - Takeuchi, Yasuto AU - Takeuchi Y AD - Division of Cancer Cell Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. FAU - Kimura, Natsuko AU - Kimura N AD - Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Murayama, Takahiko AU - Murayama T AUID- ORCID: 0000-0003-0764-8646 AD - Division of Cancer Cell Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. AD - Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Machida, Yukino AU - Machida Y AD - Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. AD - Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo 104-0045, Japan. FAU - Iejima, Daisuke AU - Iejima D AD - Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Nishimura, Tatsunori AU - Nishimura T AD - Division of Cancer Cell Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. AD - Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Terashima, Minoru AU - Terashima M AUID- ORCID: 0000-0002-5688-5181 AD - Division of Functional Genomics, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. FAU - Wang, Yuming AU - Wang Y AD - Division of Cancer Cell Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. FAU - Li, Mengjiao AU - Li M AD - Division of Cancer Cell Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. FAU - Sakamoto, Reiko AU - Sakamoto R AD - Laboratory of Developmental Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Yamamoto, Mizuki AU - Yamamoto M AD - Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Itano, Naoki AU - Itano N AUID- ORCID: 0000-0002-9276-7959 AD - Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan. FAU - Inoue, Yusuke AU - Inoue Y AUID- ORCID: 0000-0001-7250-8303 AD - Department of Diagnostic Radiology, Kitasato University of School of Medicine, Sagamihara City 252-0373, Japan. FAU - Ito, Masataka AU - Ito M AD - Department of Anatomy, National Defense Medical College, Tokorozawa 359-8513, Japan. FAU - Yoshida, Nobuaki AU - Yoshida N AD - Laboratory of Developmental Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Inoue, Jun-Ichiro AU - Inoue JI AD - Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Akashi, Koichi AU - Akashi K AD - Department of Medicine and Biosystemic Science, Graduate School of Medicine, Kyushu University, Fukuoka 812-8582, Japan. FAU - Saya, Hideyuki AU - Saya H AD - Division of Gene Regulation, Institute of Advanced Medical Research, Keio University, Tokyo 160-8582, Japan. FAU - Fujita, Koji AU - Fujita K AD - Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan. FAU - Kuroda, Masahiko AU - Kuroda M AD - Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan. FAU - Kitabayashi, Issay AU - Kitabayashi I AD - Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo 104-0045, Japan. FAU - Voon, Dominic AU - Voon D AD - Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. FAU - Suzuki, Takeshi AU - Suzuki T AUID- ORCID: 0000-0002-1737-0900 AD - Division of Functional Genomics, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. FAU - Tojo, Arinobu AU - Tojo A AUID- ORCID: 0000-0001-9016-1948 AD - Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. FAU - Gotoh, Noriko AU - Gotoh N AUID- ORCID: 0000-0003-3733-260X AD - Division of Cancer Cell Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan; ngotoh@staff.kanazawa-u.ac.jp. AD - Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Cytokines) RN - 0 (FRS3 protein, human) RN - 0 (Frs3 protein, mouse) RN - 0 (NF-kappa B) RN - EC 2.7.10.1 (Erbb2 protein, mouse) RN - EC 2.7.10.1 (Receptor, ErbB-2) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/immunology/*metabolism MH - Animals MH - Breast Neoplasms/*etiology/immunology/*metabolism MH - Carcinogenesis MH - Cytokines/metabolism MH - Female MH - Humans MH - Inflammation/etiology/metabolism MH - Mammary Neoplasms, Experimental/*etiology/immunology/*metabolism MH - Mammary Tumor Virus, Mouse MH - Mice MH - Mice, Knockout MH - NF-kappa B/metabolism MH - Pregnancy MH - Receptor, ErbB-2/metabolism MH - Retroviridae Infections MH - Tumor Microenvironment/immunology MH - Tumor Virus Infections PMC - PMC8639355 OTO - NOTNLM OT - FRS3 OT - NF-kappaB OT - breast cancer OT - cancer-associated fibroblasts OT - premalignant inflammation COIS- The authors declare no competing interest. EDAT- 2021/10/20 06:00 MHDA- 2021/12/15 06:00 PMCR- 2021/10/18 CRDT- 2021/10/19 05:55 PHST- 2021/08/19 00:00 [accepted] PHST- 2021/10/19 05:55 [entrez] PHST- 2021/10/20 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/10/18 00:00 [pmc-release] AID - 2103658118 [pii] AID - 202103658 [pii] AID - 10.1073/pnas.2103658118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Oct 26;118(43):e2103658118. doi: 10.1073/pnas.2103658118.