Imatinib mesylate enhances the malignant behavior of human breast carcinoma cells.
OBJECTIVE
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 × 10(4) 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.
Rappa
Germana
G
Department of Drug Development, Nevada Cancer Institute, One Breakthrough Way, Las Vegas, NV 89135, USA.
Anzanello
Fabio
F
Lorico
Aurelio
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology / Q000633:toxicity*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D051153:Wnt Proteins; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3