title: ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines.
abstract: The non-receptor tyrosine kinase ABL drives myeloid progenitor expansion in human chronic myeloid leukemia. ABL inhibition by the tyrosine kinase inhibitor nilotinib is a first-line treatment for this disease. Recently, ABL has also been implicated in the transforming properties of solid tumors, including triple negative (TN) breast cancer. TN breast cancers are highly metastatic and several cell lines derived from these tumors display high invasive activity in vitro. This feature is associated with the activation of actin-rich membrane structures called invadopodia that promote extracellular matrix degradation. Here, we investigated nilotinib effect on the invasive and migratory properties of different TN breast cancer cell lines. Nilotinib decreased both matrix degradation and invasion in the TN breast cancer cell lines MDA-MB 231 and MDA-MB 468. However, and unexpectedly, nilotinib increased by two-fold the invasive properties of the TN breast cancer cell line BT-549 and of Src-transformed fibroblasts. Both display much higher levels of ABL kinase activity compared to MDA-MB 231. Similar effects were obtained by siRNA-mediated down-regulation of ABL expression, confirming ABL central role in this process. ABL anti-tumor effect in BT-549 cells and Src-transformed fibroblasts was not dependent on EGF secretion, as recently reported in neck and squamous carcinoma cells. Rather, we identified the TRIO-RAC1 axis as an important downstream element of ABL activity in these cancer cells. In conclusion, the observation that TN breast cancer cell lines respond differently to ABL inhibitors could have implications for future therapies.
authors: Centre de Recherche de Biochimie Macromoléculaire CNRS UMR5237, University of Montpellier, Montpellier, 34000, France.
authors: Clément
authors: C
authors: Chevalier
authors: Centre de Recherche de Biochimie Macromoléculaire CNRS UMR5237, University of Montpellier, Montpellier, 34000, France.
authors: Aude
authors: A
authors: Cannet
authors: Centre de Recherche de Biochimie Macromoléculaire CNRS UMR5237, University of Montpellier, Montpellier, 34000, France.
authors: Simon
authors: S
authors: Descamps
authors: Centre de Recherche de Biochimie Macromoléculaire CNRS UMR5237, University of Montpellier, Montpellier, 34000, France.
authors: Audrey
authors: A
authors: Sirvent
authors: Centre de Recherche de Biochimie Macromoléculaire CNRS UMR5237, University of Montpellier, Montpellier, 34000, France.
authors: Valérie
authors: V
authors: Simon
authors: Centre de Recherche de Biochimie Macromoléculaire CNRS UMR5237, University of Montpellier, Montpellier, 34000, France.
authors: Serge
authors: S
authors: Roche
authors: Centre de Biochimie Structurale, CNRS UMR 5048, INSERM UMR 1054, University of Montpellier, Montpellier, 34090, France.
authors: Christine
authors: C
authors: Benistant
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066257:Heparin-binding EGF-like Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein; C498826:nilotinib