title: Suppression of Neu-induced mammary tumor growth in cyclin D1 deficient mice is compensated for by cyclin E.
abstract: Amplification and/or overexpression of the receptor tyrosine kinase HER2/Neu and the cell cycle regulatory gene cyclin D1 are frequently associated with human breast cancer. We studied the functional significance of cyclin D1 in Neu-induced mammary oncogenesis by developing mice overexpressing either wild-type or mutant Neu in a cyclin D1 deficient background. The absence of cyclin D1 suppresses mammary tumor formation induced by the wild-type or activated mutant form of Neu, which promote multi- and single-step progression of tumorigenesis, respectively. These data indicate that cyclin D1 is preferentially required for Neu-mediated signal transduction pathways in mammary oncogenesis. Significantly, 35% of mutant Neu/cyclin D1(-/-) mice regained mammary tumor potential due to compensation by cyclin E. Thus, shared targets of cyclins D1 and E are important in modulating Neu function in mammary tumorigenesis. Our results imply that the combinatorial inhibition of cyclins D1 and E might be useful in the treatment of malignancies induced by Neu.
authors.affiliation: Laboratory of Cancer Genomics, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, SC 29425, USA.
authors.forename: Damon B
authors.initials: DB
authors.lastname: Bowe
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Kenney
authors.forename: Yair
authors.initials: Y
authors.lastname: Adereth
authors.forename: Ioanna G
authors.initials: IG
authors.lastname: Maroulakou
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000517:prevention & control; D000818:Animals; D019938:Cyclin D1 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D019927:Cyclin E / Q000502:physiology*; D005260:Female; D018734:Genes, erbB-2; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction; D013489:Suppression, Genetic
chemical_list: D019938:Cyclin D1; D019927:Cyclin E; D018719:Erb-b2 Receptor Tyrosine Kinases