title: Downregulation of CXCR4 in Metastasized Breast Cancer Cells and Implication in Their Dormancy.
abstract: Our understanding of the mechanism of cancer dormancy is emerging, but the underlying mechanisms are not fully understood. Here we analyzed mouse xenograft tumors derived from human breast cancer tissue and the human breast cancer cell line MDA-MB-231 to identify the molecules associated with cancer dormancy. In immunohistological examination using the proliferation marker Ki-67, the tumors included both proliferating and dormant cancer cells, but the number of dormant cells was remarkably increased when they metastasized to the lung. In the gene expression analysis of the orthotopic cancer cells by a single-cell multiplex real-time quantitative reverse transcription PCR followed by flow cytometric analysis, restrained cellular proliferation was associated with downregulation of the chemokine receptor CXCR4. In the immunohistological and flow cytometric analyses, the expression level of CXCR4 in the metastasized cancer cells was decreased compared with that in the cancer cells in orthotopic tumors, although the expression level of the CXCR4 ligand CXCL12 was not reduced in the lung. In addition, the proliferation of the metastasized cancer cells was further decreased by the CXCR4 antagonist administration. In the ex vivo culture of the metastasized cancer cells, the expression level of CXCR4 was increased, and in the xenotransplantation of ex vivo cultured cancer cells, the expression level of CXCR4 was again decreased in the metastasized cancer cells in the lung. These findings indicate that CXCR4 is downregulated in metastasized breast cancer cells and implicated in their dormancy.
authors.affiliation: Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nobutani
authors.affiliation: Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shimono
authors.affiliation: Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Kitayama
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Minami
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Momose
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Fukuoka, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Miyawaki
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Azuma
authors.affiliation: Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takai
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D054377:Chemokine CXCL12 / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4