title: Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists.
abstract: 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.
authors.affiliation: Department of Cell and Cancer Biology, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.forename: Thai Hong
authors.initials: TH
authors.lastname: Tran
authors.forename: Catriona M
authors.initials: CM
authors.lastname: McNeil
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Burd
authors.forename: Susan M
authors.initials: SM
authors.lastname: Henshall
authors.forename: Fransiscus E
authors.initials: FE
authors.lastname: Utama
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witkiewicz
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D016213:Cyclins / Q000235:genetics* / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056741:Cyclin D; D016213:Cyclins; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D002945:Cisplatin