title: Progressive loss of Syk and abnormal proliferation in breast cancer cells.
abstract: The tumor suppressor gene Syk tyrosine kinase is absent or reduced in invasive breast cancer tissues and cell lines; its loss in breast tissues is linked to poor prognosis and metastasis. Also, evidence shows that in vitro Syk is involved in regulating proliferation. Here, we show by in situ hybridization on breast tissue sections that the loss of Syk expression is progressive during tumor development. Strikingly, Syk is already partially lost in normal epithelial tissue adjacent to the cancer lesion. In vivo, cell proliferation (as measured by the proliferative index Ki67) increased from normal to ductal carcinoma in situ to invasive, whereas Syk in situ staining in the same tissues decreased. In vitro, the presence of Syk was associated with reduced cell proliferation in an epidermal growth factor receptor-overexpressing breast cancer cell line, BT549, whereas changes in apoptosis were undetected. Concomitantly, the kinase activity of the proto-oncogene Src was reduced by approximately 30%. A 5-fold increase in abnormal mitoses was observed in the Syk-transfected cells compared with vector control. We propose that Syk is involved in the regulation of cell proliferation, possibly by controlling mechanisms of mitosis and cytokinesis via Src signal transduction pathway(s). Because of its progressive and early loss during tumor onset and development, monitoring of Syk loss in breast epithelial cells by noninvasive techniques such as ductal lavage may be a powerful tool for screening purposes.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Moroni
authors.forename: Viatcheslav
authors.initials: V
authors.lastname: Soldatenkov
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gerald
authors.initials: G
authors.lastname: Stoica
authors.forename: Edmund
authors.initials: E
authors.lastname: Gehan
authors.forename: Banafsheh
authors.initials: B
authors.lastname: Rashidi
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Metin
authors.initials: M
authors.lastname: Ozdemirli
authors.forename: Susette C
authors.initials: SC
authors.lastname: Mueller
mesh_terms: D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000072377:Syk Kinase; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases