title: Cyclin D1 overexpression induces progestin resistance in T-47D breast cancer cells despite p27(Kip1) association with cyclin E-Cdk2.
abstract: Long-term growth inhibition, arrest in G(1) phase and reduced activity of both cyclin D1-Cdk4 and cyclin E-Cdk2 are elicited by progestin treatment of breast cancer cells in culture. Decreased cyclin expression, induction of p18(INK4c) and increased association of the CDK inhibitors p21(WAF1/Cip1) and p27(Kip1) with cyclin E-Cdk2 have been implicated in these responses. To determine the role of decreased cyclin expression, T-47D human breast cancer cells constitutively expressing cyclin D1 or cyclin E were treated with the progestin ORG 2058. Overexpression of cyclin E had only a modest effect on growth inhibition. Although cyclin E expression was maintained during progestin treatment, cyclin E-Cdk2 activity decreased by approximately 60%. This was accompanied by p27(Kip1) association with cyclin E-Cdk2, indicating that both cyclin E down-regulation and p27(Kip1) recruitment contribute to the decrease in activity. In contrast, overexpression of cyclin D1 induced progestin resistance and cell proliferation continued despite decreased cyclin E-Cdk2 activity. Progestin treatment of cyclin D1-overexpressing cells was associated with increased p27(Kip1) association with cyclin E-Cdk2. Thus the ability of cyclin D1 to confer progestin resistance does not depend on sequestration of p27(Kip1) away from cyclin E-Cdk2, providing evidence for a critical function of cyclin D1 other than as a high-capacity "sink" for p27(Kip1). These data indicate that regulation of cyclin D1 is a critical element of progestin inhibition in breast cancer cells and suggest that breast cancers overexpressing cyclin D1 may respond poorly to progestin therapy.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia. e.musgrove@garvan.org.au
authors.forename: E A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: L J
authors.initials: LJ
authors.lastname: Hunter
authors.forename: C S
authors.initials: CS
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Swarbrick
authors.forename: R
authors.initials: R
authors.lastname: Hui
authors.forename: R L
authors.initials: RL
authors.lastname: Sutherland
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism*; D019927:Cyclin E / Q000096:biosynthesis / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016193:G1 Phase; D010766:Phosphorylation; D011233:Precipitin Tests; D011282:Pregnenediones / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011379:Prognosis; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D011282:Pregnenediones; D045167:Progesterone Congeners; D011372:Progestins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases