title: Involvement of Lyn and the atypical kinase SgK269/PEAK1 in a basal breast cancer signaling pathway.
abstract: Basal breast cancer cells feature high expression of the Src family kinase Lyn that has been implicated in the pathogenicity of this disease. In this study, we identified novel Lyn kinase substrates, the most prominent of which was the atypical kinase SgK269 (PEAK1). In breast cancer cells, SgK269 expression associated with the basal phenotype. In primary breast tumors, SgK269 overexpression was detected in a subset of basal, HER2-positive, and luminal cancers. In immortalized MCF-10A mammary epithelial cells, SgK269 promoted transition to a mesenchymal phenotype and increased cell motility and invasion. Growth of MCF-10A acini in three-dimensional (3D) culture was enhanced upon SgK269 overexpression, which induced an abnormal, multilobular acinar morphology and promoted extracellular signal-regulated kinase (Erk) and Stat3 activation. SgK269 Y635F, mutated at a major Lyn phosphorylation site, did not enhance acinar size or cellular invasion. We show that Y635 represents a Grb2-binding site that promotes both Stat3 and Erk activation in 3D culture. RNA interference-mediated attenuation of SgK269 in basal breast cancer cells promoted acquisition of epithelial characteristics and decreased anchorage-independent growth. Together, our results define a novel signaling pathway in basal breast cancer involving Lyn and SgK269 that offers clinical opportunities for therapeutic intervention.
authors: Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors: David R
authors: DR
authors: Croucher
authors: Falko
authors: F
authors: Hochgräfe
authors: Luxi
authors: L
authors: Zhang
authors: Ling
authors: L
authors: Liu
authors: Ruth J
authors: RJ
authors: Lyons
authors: Danny
authors: D
authors: Rickwood
authors: Carole M
authors: CM
authors: Tactacan
authors: Brigid C
authors: BC
authors: Browne
authors: Naveid
authors: N
authors: Ali
authors: Howard
authors: H
authors: Chan
authors: Robert
authors: R
authors: Shearer
authors: David
authors: D
authors: Gallego-Ortega
authors: Darren N
authors: DN
authors: Saunders
authors: Alexander
authors: A
authors: Swarbrick
authors: Roger J
authors: RJ
authors: Daly
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C573947:PEAK1 protein, human; D011505:Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases