title: C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis.
abstract: The proto-oncogene, c-src, has been implicated in the tumorigenesis in breast cancer. However, the relationship of c-src with distant metastasis is unclear. Moreover, the role of c-src in organ-preferential metastasis of breast cancer is unknown. Because breast cancer has a strong predilection for metastasizing to bone, we examined the role of c-src in bone metastases using an animal model in which inoculation of the MDA-231 human breast cancer cells into the left cardiac ventricle preferentially developed osteolytic bone metastases in female nude mice. A clone of the MDA-231 with the increased capacity of bone metastasis exhibited elevated c-src tyrosine kinase (TK) activity compared with parental cells. MDAsrc527 cells caused significantly increased size of the osteolytic bone metastases with increased number of osteoclasts and mitotic cancer cells compared with MDA-231EV or MDAsrcWT. In contrast, MDAsrc295 cells caused impaired metastases to bone. Of note, mice inoculated with MDAsrc295 cells via tail vein developed reduced lung metastases and prolonged survival compared with mice with MDA-231EV cells, suggesting that c-src TK is unlikely to play a specific role in bone metastases. The growth in vitro and in vivo and production of parathyroid hormone-related protein, a key cytokine in the pathogenesis of osteolytic bone metastases in breast cancer, were promoted in MDAsrc527 and diminished in MDAsrc295. These results suggest that c-src TK is associated with the capacity of breast cancer to metastasize to bone through regulating cell growth and parathyroid hormone-related protein production. Our results together with the fact that c-src is an essential molecule for bone resorption by osteoclasts, which are central players in osteolytic bone metastases, support the notion that c-src TK is a potential target molecule for designing novel therapeutic interventions, especially for bone metastases in breast cancer.
authors.affiliation: Osaka University, Graduate School of Medicine, Department of Orthopaedics, Suita, Osaka 565-0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Myoui
authors.forename: Riko
authors.initials: R
authors.lastname: Nishimura
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Williams
authors.forename: Toru
authors.initials: T
authors.lastname: Hiraga
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tamura
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Mundy
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D001862:Bone Resorption / Q000209:etiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D000081247:CSK Tyrosine-Protein Kinase; D002455:Cell Division; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D010010:Osteoclasts / Q000502:physiology; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000096:biosynthesis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D014162:Transfection; D019061:src-Family Kinases
chemical_list: C000715470:MAS1 protein, human; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D000090063:Proto-Oncogene Mas; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human