title: The β-catenin signaling pathway induces aggressive potential in breast cancer by up-regulating the chemokine CCL5.
abstract: β-Catenin signaling plays a pivotal role in the genesis of a variety of malignant tumors, but its role in breast cancer has not been fully elucidated. Here, we examined whether deregulation of β-catenin signaling is related to the aggressive characteristics of certain types of breast cancers. Analysis of cytokine levels in MDA-MB-231 cells overexpressing a constitutively active form of β-catenin (CAβ-catenin) revealed a higher level of CCL5 expression. Cells transfected with CAβ-catenin or stimulated with recombinant CCL5 exhibited increased cell invasion activity and spheroid formation in vitro. Furthermore, CAβ-catenin-transfected MDA-MB-231 cells formed larger tumor masses that contained more Ki-67-positive cells and infiltrating lymphocytes than did the control cells. An inhibitor of CCR5 and a pan-CXCR neutralizing antibody dramatically reduced CAβ-catenin-promoted activities. In addition to CCL5, 6-BIO, a chemical activator of β-catenin, induced cell invasion and spheroid formation in MDA-MB-231 cells. Furthermore, high levels of nuclear β-catenin accumulation were detected in breast cancer in patients with metastasis but not in those without metastasis. Nuclear β-catenin localization is related to increased CCL5 production in breast cancer. These findings suggest that β-catenin expression enhances tumor progression via chemokine production in breast cancers and that β-catenin signaling is a critical regulator of the aggressive traits of breast cancers.
authors.affiliation: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. Electronic address: yasuhara.r@dent.showa-u.ac.jp.
authors.forename: Rika
authors.initials: R
authors.lastname: Yasuhara
authors.affiliation: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Tarou
authors.initials: T
authors.lastname: Irié
authors.affiliation: Division of Breast Surgical Oncology, Department of Surgery, Showa University, Tokyo, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Division of Breast Surgical Oncology, Department of Surgery, Showa University, Tokyo, Japan.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Division of Breast Surgical Oncology, Department of Surgery, Showa University, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miwa
authors.affiliation: Department Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Breast Center, Kameda Medical Center, Chiba, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsunoda
authors.affiliation: Division of Breast Surgical Oncology, Department of Surgery, Showa University, Tokyo, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mishima
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin
chemical_list: C483024:CCL5 protein, human; C495270:CTNNB1 protein, human; D018946:Chemokine CCL5; D051176:beta Catenin
keywords: Breast cancer; CCL5; Cytokines; Metastasis; β-Catenin