Activation of Abl Tyrosine Kinases Promotes Invasion of Aggressive Breast Cancer Cells

Abstract

The Abl family of nonreceptor tyrosine kinases consists of two related proteins, c-Abl and Abl-related gene (Arg). Activated forms of the Abl kinases (BCR-Abl, Tel-Abl, and Tel-Arg) induce the development of human leukemia; it is not known, however, whether Abl kinases are activated in solid tumors or whether they contribute to tumor development or progression. Previously, we showed that Abl kinases are activated downstream of growth factor receptors, Src family kinases, and phospholipase C;1 (PLC;1) in fibroblasts and influence growth factor-mediated proliferation, membrane ruffling, and migration. Growth factor receptors, Src kinases, and PLC;1 are deregulated in many solid tumors and drive tumor invasion and metastasis. In this study, we found that Abl kinases are constitutively activated, in highly invasive breast cancer cell lines, downstream of deregulated ErbB receptors and Src kinases. Furthermore, activation of Abl kinases promotes breast cancer cell invasion, as treatment of cells with the Abl kinase inhibitor, STI571, or silencing c-Abl and Arg expression with RNA interference dramatically inhibits Matrigel invasion. This is the first evidence that (a) Abl kinases are deregulated and activated in a nonhematopoietic cancer, (b) activation of Abl kinases in breast cancer cells occurs via a novel mechanism, and (c) constitutive activation of Abl kinases promotes invasion of breast cancer cells. These data suggest that pharmacologic inhibitors targeted against Abl kinases could potentially be useful in preventing breast cancer progression in tumors harboring activated Abl kinases. (Cancer Res 2006; 66(11): 5648-55)

Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1

“…Further, the facts that c-Abl tyrosine kinase can be activated downstream of EGFR via Src kinase (Plattner et al, 1999) and c-Abl plays a role in breast cancers overexpressing EGFR (Srinivasan and Plattner, 2006) strengthen the possibility of c-Abl contributing to the oncogenicity of NSCLC, especially since our studies show that the deficiency of expression of the functional FUS1 TSG contributes to increased active c-Abl kinase. Further, a recent study has shown that activated Abl kinase has a novel role in the regulation of EGFR endocytosis.…”

“…A recent report has shown that c-Abl tyrosine kinase is activated in aggressive human breast cancer cell lines (Srinivasan and Plattner, 2006). Activation of c-Abl was linked to EGFR expression and activation in the breast cancer cell lines (Srinivasan and Plattner, 2006).…”

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

“…In the current study, these cell lines are among those highly sensitive to dasatinib and are classified as post-EMT due to their expression of high levels of vimentin. Also of interest is the observation that the basal cell line MDA-MB-468 was one of only 3 basal cell lines that we found to be resistant to dasatinib and in the study implicating abl this cell line had a low level of abl activation [41]. These data raise the possibility that abl inhibition is another potential mechanism of dasatinib activity in basal breast cancer cell lines.…”

“…An alternative explanation for the current results could be based on new data implicating abl in breast cancer. Evaluation of abl activation in a panel of 8 breast cancer cell lines has shown constitutive activation of abl in ''aggressive breast cancer cells'' without increases in abl gene expression [41]. These cell lines included many that were evaluated in our panel, including MDA-MB-468, MCF-7, BT-474, SK-BR-3, MDA-MB-231, MDA-MB-453, and UACC-893.…”

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

“…The activated forms of Abl kinases (BCR-Abl, Tel-Abl and Tel-Arg) induce the development of human leukemia (Skorski et al, 1998;Druker et al, 2001;Pendergast, 2001;Kim et al, 2004). Recent studies suggest that Abl kinases are constitutively activated in breast cancer cells and constitutive activation of Abl kinases promotes breast cancer cell invasion (Srinivasan and Plattner, 2006;Jallal et al, 2007;Srinivasan et al, 2008). Although the mechanism by which BCR-Abl drives leukemiagenesis is well understood, little is known regarding how Abl promotes progression of solid tumors.…”