title: Src kinases catalytic activity regulates proliferation, migration and invasiveness of  MDA-MB-231 breast cancer cells.
abstract: SFKs are frequently deregulated in cancer where they control cellular proliferation, migration, survival and metastasis. Here we study the role of SFKs catalytic activity in triple-negative/basal-like and metastatic human breast cancer MDA-MB-231 cells employing three well-established inhibitors: Dasatinib, PP2 and SU6656. These compounds inhibited migration and invasion. Concomitantly, they reduced Fak, paxillin, p130CAS, caveolin-1 phosphorylation and altered cytoskeletal structures. They also inhibited cell proliferation, but in different manners. Dasatinib and PP2 increased p27(Kip1) expression and reduced c-Myc levels, restraining G1–S transition. In contrast, SU6656 did not modify p27(Kip1) expression, slightly altered c-Myc levels and generated polyploid multinucleated cells, indicating inhibition of cytokinesis. These later effects were also observed in SYF fibroblasts, suggesting a SFKs-independent action. ZM447439, an Aurora B kinase inhibitor, produced similar cell cycle and morphological alterations in MDA-MB-231 cells, indicating that SU6656 blocked Aurora B kinase. This was confirmed by inhibition of histone H3 phosphorylation, the canonical Aurora B kinase substrate. Furthermore, hierarchical clustering analysis of gene expression profiles showed that SU6656 defined a set of genes that differed from Dasatinib and PP2. Additionally, Gene Set Enrichment Analyses revealed that SU6656 significantly reduces the Src pathway. Together, these results show the importance of SFKs catalytic activity for MDA-MB-231 proliferation, migration and invasiveness. They also illustrate that SU6656 acts as dual SFKs and Aurora B kinase inhibitor, suggesting its possible use as a therapeutic agent in breast cancer.
authors.affiliation: Dpto. Biología del Cáncer, Instituto de Investigaciones Biomédicas A. Sols (CSIC/UAM), Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Sánchez-Bailón
authors.forename: Annarica
authors.initials: A
authors.lastname: Calcabrini
authors.forename: Daniel
authors.initials: D
authors.lastname: Gómez-Domínguez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morte
authors.forename: Esther
authors.initials: E
authors.lastname: Martín-Forero
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.forename: Agnese
authors.initials: A
authors.lastname: Molinari
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Jorge
authors.initials: J
authors.lastname: Martín-Pérez
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D005260:Female; D006801:Humans; D007211:Indoles; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D051419:Paxillin / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D007211:Indoles; D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C416927:SU 6656; D013449:Sulfonamides; D013844:Thiazoles; D019061:src-Family Kinases; D000069439:Dasatinib