title: Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence.
abstract: BACKGROUND
  Androgen withdrawal is a standard therapy for prostate cancer that results in a decrease in tumor volume and a decline in serum prostate-specific antigen in the majority of patients. To understand the factors associated with regression of prostate cancers after androgen withdrawal, we studied cell cycle regulator changes in the CWR22 human prostate cancer xenograft model.
  
  
  METHODS
  Established tumors in nude athymic BALB/c mice were sampled at various times after androgen withdrawal and after the development of androgen independence. Changes in the expression of cell cycle regulators were categorized into early and mid-to-late events.
  
  
  CONCLUSIONS
  Early events included a decrease in androgen receptor expression, followed by a short-term increase in expression of the p53 and p21/WAF1 proteins and a marked decrease in the Ki67 proliferative index. Mid-to-late events included progressive and sustained increases in p27 and p16 protein expression, a decrease in retinoblastoma protein expression, and an increase in the transcription factor E2F1. Changes in apoptosis (programmed cell death) were not observed at any time after androgen withdrawal. These data suggest that androgen withdrawal results in a cell stress response, in which increased p53 protein produces a cell cycle arrest, without activation of p53-mediated apoptosis. The proliferative index is further decreased through the action of the cyclin-dependent kinase inhibitors p27 and p16. Androgen-independent sublines emerged 80-400 days after androgen withdrawal, and these sublines had variable growth phenotypes but were associated with mdm2 protein overexpression and increased expression of cyclin D1. These results indicate that tumor regression in this human prostate cancer model is due to cell cycle arrest rather than to apoptosis and that the emergence of androgen independence is associated with a release from cell cycle arrest.
authors.affiliation: Department of Medicine, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. d-agus@ski.mskcc.org
authors.forename: D B
authors.initials: DB
authors.lastname: Agus
authors.forename: C
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: W
authors.initials: W
authors.lastname: Fox
authors.forename: M
authors.initials: M
authors.lastname: Drobnjak
authors.forename: A
authors.initials: A
authors.lastname: Koff
authors.forename: D W
authors.initials: DW
authors.lastname: Golde
authors.forename: H I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D013997:Time Factors; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000728:Androgens; D000911:Antibodies, Monoclonal; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011944:Receptors, Androgen; C058992:Tagln protein, mouse; D016159:Tumor Suppressor Protein p53