ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines.

Clément Chevalier,Simon Descamps,Serge Roche,Audrey Sirvent,Aude Cannet,Valérie Simon,Christine Benistant,Rafael Garcia-Mata

doi:10.1371/journal.pone.0118854

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.

Highlights

Breast tumors are very heterogeneous and can be classified in three main groups based on their molecular profile: luminal cancers that express both estrogen and progesterone receptors; HER2-positive cancers that express the tyrosine kinase receptor ERBB2; and triple negative (TN) cancers in which none of these receptors is detected
We first determined whether ABL kinase inhibitors currently used in the clinic affect the invasive properties of three TN breast cancer cell lines (MDA-MB 231, BT-549, and MDA-MB 468) and of transformed cells the reference model cell line 3T3 SrcY527F
SU6656 and dasatinib inhibited the invasive activity of all cell lines, whereas imatinib and nilotinib had an inhibitory effect only in MDA-MB 231 and MDAMB 468 cells (Fig. 1A, B and S1 Fig. A, B)

Summary

Introduction

Breast tumors are very heterogeneous and can be classified in three main groups based on their molecular profile: luminal cancers that express both estrogen and progesterone receptors; HER2-positive cancers that express the tyrosine kinase receptor ERBB2; and triple negative (TN) cancers in which none of these receptors is detected. ABL kinases form a family of ubiquitously expressed non-receptor TKs that include two members: ABL and ARG (Abl-related gene) Both proteins localize to the cell membrane, the actin cytoskeleton and the cytosol, and ABL is present in the nucleus. Like most TKs, the ABL family comprises oncogenic forms that exhibit strict cytoplasmic localization and deregulated kinase activity These include the retroviral oncoprotein v-Abl expressed by the Abelson murine leukemia virus and the human BCR-ABL fusion oncoprotein that is responsible for human chronic myeloid leukemia (CML) [6]. ABL kinases are important regulators of actin cytoskeleton remodeling during cancer cell migration and invasion [8] They are involved in invadopodia maturation by directly phosphorylating cortactin at Y421 and Y470 [9]. A recent report demonstrated that ABL kinases negatively regulate invadopodia function and cell invasion of head and neck squamous cell carcinoma, through inhibition of a heparin binding epidermal growth factorlike growth factor (HB-EGF) autocrine loop [12]

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Conclusion