Elevated expression of DecR1 impairs ErbB2/Neu-induced mammary tumor development.
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 beta-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.
Ursini-Siegel
Josie
J
Department of Medicine, McGill University, Montreal, Quebec, Canada H3A 1A1.
Rajput
Ashish B
AB
Lu
Huiling
H
Sanguin-Gendreau
Virginie
V
Zuo
Dongmei
D
Papavasiliou
Vasilios
V
Lavoie
Cynthia
C
Turpin
Jason
J
Cianflone
Katherine
K
Huntsman
David G
DG
Muller
William J
WJ
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D019085:Fluorescent Antibody Technique, Direct; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009368:Neoplasm Transplantation; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D053320:Receptors, Tumor Necrosis Factor, Member 10c / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous
D005227:Fatty Acids; D005947:Glucose; D018719:Erb-b2 Receptor Tyrosine Kinases; D053320:Receptors, Tumor Necrosis Factor, Member 10c