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Molecular and Cellular Biology, September 2007, p. 6361-6371, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.00686-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Elevated Expression of DecR1 Impairs ErbB2/Neu-Induced Mammary Tumor Development ^,

Departments of Medicine and Biochemistry, McGill University, Montreal, Quebec, Canada H3A 1A1,¹ Genetic Pathology Evaluation Centre, Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6,² Department of Physiology and Anatomy, Centre de Recherche Hopital Laval, Universite Laval, Quebec, Canada G1V 3N5³

Received 19 April 2007/ Returned for modification 29 May 2007/ Accepted 29 June 2007

Tumor cells utilize glucose as a primary energy source and require ongoing lipid biosynthesis for growth. Expression of DecR1, an auxiliary enzyme in the fatty acid ß-oxidation pathway, is significantly diminished in numerous spontaneous mammary tumor models and in primary human breast cancer. Moreover, ectopic expression of DecR1 in ErbB2/Neu-induced mammary tumor cells is sufficient to reduce levels of ErbB2/Neu expression and impair mammary tumor outgrowth. This correlates with a decreased proliferative index and reduced rates of de novo fatty acid synthesis in DecR1-expressing breast cancer cells. Although DecR1 expression does not affect glucose uptake in ErbB2/Neu-transformed cells, sustained expression of DecR1 protects mammary tumor cells from apoptotic cell death following glucose withdrawal. Moreover, expression of catalytically impaired DecR1 mutants in Neu-transformed breast cancer cells restored Neu expression levels and increased mammary tumorigenesis in vivo. These results argue that DecR1 is sufficient to limit breast cancer cell proliferation through its ability to limit the extent of oncogene expression and reduce steady-state levels of de novo fatty acid synthesis. Furthermore, DecR1-mediated suppression of tumorigenesis can be uncoupled from its effects on Neu expression. Thus, while downregulation of Neu expression may contribute to DecR1-mediated tumor suppression in certain cell types, this is not an obligate event in all Neu-transformed breast cancer cells.

Published ahead of print on 16 July 2007.

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