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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2011

01-04-2011 | Original Article

Imatinib mesylate enhances the malignant behavior of human breast carcinoma cells

Authors: Germana Rappa, Fabio Anzanello, Aurelio Lorico

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2011

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Abstract

Purpose

Imatinib mesylate (Imatinib), clinically employed for chronic myeloid leukemia and gastrointestinal stromal tumors, is a selective inhibitor of the tyrosine kinases, c-abl, c-kit and PDGFRs. Due to the frequent expression of these genes in breast cancer cells, the clinical efficacy of Imatinib has recently been investigated in patients with advanced and metastatic breast cancer. Here, we have studied the effects of Imatinib on human MA-11 breast carcinoma cells, expressing both c-abl and PDGFRbeta, in vitro and in mouse xenografts.

Methods

The effects of Imatinib mesylate on the human MA-11 breast carcinoma cell line were studied in vitro and in xenografts.

Results

Daily intraperitoneal treatment with 60 mg/kg Imatinib for 9 days of athymic nude mice pre-implanted subcutaneously with MA-11 cells did not result in an anti-tumor effect, but rather increased the take rate of 3 × 104 cells from 30.8 to 84.6% and caused the appearance of large abdominal masses in 30% of mice. To investigate the mechanism(s) of the observed effects of Imatinib on MA-11 tumors, we exposed the cells in vitro to Imatinib for 9 days. The surviving population, expanded in culture, showed increased motility and over-expressed a set of genes associated with aggressive behavior. Also, several genes belonging to the Wnt and the MAPK pathway were differentially expressed. In promoter activation assays, Imatinib increased the promoter activity driven by both Wnt and MAPK/ERK-1/2.

Conclusions

Our data suggest caution in the clinical use of Imatinib in breast cancer patients; the comparison of Imatinib-surviving breast cancer cells with parental cells may help define the regulatory pathways involved in the increased malignancy of residual tumor cells that survive therapy, ultimately providing important therapeutic targets.
Appendix
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Metadata
Title
Imatinib mesylate enhances the malignant behavior of human breast carcinoma cells
Authors
Germana Rappa
Fabio Anzanello
Aurelio Lorico
Publication date
01-04-2011
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-010-1394-x

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