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Cyclin D1b Is Aberrantly Regulated in Response to Therapeutic Challenge and Promotes Resistance to Estrogen Antagonists

¹ Kimmel Cancer Center; ² Department of Cancer Biology and ³ Department of Pathology, Thomas Jefferson University, Philadelphia Pennsylvania; ⁴ Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW; ⁵ Department of Anatomical Pathology, South Eastern Area Laboratory Service, St. George Hospital, Sydney, NSW; ⁶ National Institutes of Environmental Health Science, Research Triangle Park, North Carolina; and ⁷ Department of Cell and Cancer Biology, University of Cincinnati, Cincinnati, Ohio

Requests for reprints: Erik S. Knudsen, 233 South 10th Street, BLSB-Room 1002, Philadelphia, PA 19107. Phone: 513-558-8885; E-mail: eknudsen{at}kimmelcancercenter.org.

Key Words: breast cancer • cell cycle • estrogen antagonist • therapy • CDK4 • RB

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. [Cancer Res 2008;68(14):5628–38]

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