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Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists.


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.

Type Journal
Authors 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 ES.
Published Date 2008-07-15
Published Volume 14
Published Issue 68
Published Pages 5628-5638
Status Published in-print
DOI 10.1158/0008-5472.CAN-07-3170
URL link to publisher's version
OpenAccess link to author's accepted manuscript version