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(American Journal of Pathology. 1999;155:1861-1867.)
© 1999 American Society for Investigative Pathology

Short Communications

Overexpression of Bcl-xL Promotes Chemotherapy Resistance of Mammary Tumors in a Syngeneic Mouse Model

Rebecca Liu*, Carmen Page*, David R. Beidler{dagger}, Max S. Wicha{dagger} and Gabriel Núñez{ddagger}

From the Departments of Obstetrics and Gynecology,*
Internal Medicine,{dagger}
and Pathology,{ddagger}
Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan

Bcl-xL, a prosurvival member of the Bcl-2 family that is expressed in many tumors, represses apoptosis induced by chemotherapeutic drugs in vitro. However, the contribution of apoptosis and prosurvival Bcl-2-related proteins to chemotherapy resistance in vivo is unknown and has been challenged by recent results with clonogenic survival assays. To test the ability of Bcl-xL to provide chemotherapy resistance to tumors, we transfected the mouse bcl-xL gene into the tumorigenic SCK mammary cell line and assessed the response of tumor cells to chemotherapeutic drugs in clonogenic assays and in a syngeneic mouse model. Bcl-xL conferred protection on SCK cells against methotrexate at certain drug concentrations, but not at all against 5-fluorouracil in clonogenic survival assays in vitro. Injection of SCK cells transfected with Bcl-xL or control plasmid in the mammary fat pads of syngeneic recipient mice resulted in tumors of similar size. However, although the volume of control tumors regressed up to 80% after 4 to 5 days of chemotherapy, SCK tumors expressing Bcl-xL did not regress and continued to grow in the presence of methotrexate or 5-fluorouracil. In addition, numbers of apoptotic cells were significantly higher in control tumors as compared to Bcl-xL-expressing tumors in animals treated with methotrexate or 5-fluorouracil. These results provide evidence that inhibition of apoptosis through Bcl-xL overexpression can promote resistance to chemotherapy in tumors in vivo.




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