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

Abstract

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 β-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.

SUPPLEMENTAL MATERIAL

We gratefully acknowledge members of the Muller laboratory for helpful discussions along with Peter Siegel and Richard Marcotte for critical reading of the manuscript. We are also grateful to Bart Maslikowski for isolation of the DecR1 cDNA, Marilene Paquet for histological evaluation, David Dankort and Lina Jung for initial observations pertaining to DecR1 action in fibroblasts, and Samuel Leung for assistance in the TMA analysis. We thank Marcin Bakinowski and Jo-Ann Bader for their histological services.

This work was supported by grants from the CBCRA and CIHR. W.J.M. is supported by a CRC chair in molecular oncology.