Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists. Cancer Res 2008 Jul 15;68(14):5628-38
Date
07/18/2008Pubmed ID
18632615Pubmed Central ID
PMC8220573DOI
10.1158/0008-5472.CAN-07-3170Scopus ID
2-s2.0-48649103464 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
Cyclin D1 is a key mediator of cell cycle progression that is aberrantly regulated in multiple cancers, especially in breast cancers. A number of studies have indicated that a polymorphism in a splice donor site in the cyclin D1 gene is associated with alternative splicing and the production of the alternative cyclin D1b transcript. Furthermore, this polymorphism is selectively associated with disease outcomes. However, relatively little is known regarding the protein product of the alternatively spliced message, cyclin D1b. Using antibodies specific for cyclin D1b, it was found that this protein is readily detectable in a number of cancer cell lines and primary breast cancers. Whereas cyclin D1b interacts with cyclin-dependent kinase 4 (CDK4), it is relatively inefficient at mediating RB phosphorylation and cell cycle progression in model systems due to the lack of exon 5 of cyclin D1-encoded sequences. However, cyclin D1b protein levels are not significantly attenuated by DNA damage or antiestrogen treatment, indicating that the protein may have significant effect on the response to such therapeutic modalities. Whereas enforced expression of cyclin D1b was not sufficient to abrogate DNA damage checkpoint responses, it did efficiently overcome cell cycle arrest mediated by antiestrogen therapeutics. This action of cyclin D1b was not associated with effects on estrogen receptor activity, but was rather dependent on functional association with CDK4. Combined, these studies indicate that the cyclin D1b protein is aberrantly regulated and could contribute to therapeutic failure in the context of ER-positive breast cancer.
Author List
Wang Y, Dean JL, Millar EK, Tran TH, McNeil CM, Burd CJ, Henshall SM, Utama FE, Witkiewicz A, Rui H, Sutherland RL, Knudsen KE, Knudsen ESMESH terms used to index this publication - Major topics in bold
Antineoplastic AgentsBreast Neoplasms
Cell Line, Tumor
Cisplatin
Cyclin D
Cyclin-Dependent Kinase 4
Cyclins
Drug Resistance, Neoplasm
Estrogen Antagonists
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Phosphorylation
Polymorphism, Genetic
Receptors, Estrogen
