Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation

Craig J. Burd, Christin E. Petre, Lisa M. Morey, Ying Wang, Monica P. Revelo, Christopher A. Haiman, Shan Lu, Cecilia M. Fenoglio-Preiser, Jiwen Li, Erik S. Knudsen, Jiemin Wong, Karen E. Knudsen

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Cyclin D1 is a multifaceted regulator of both transcription and cell-cycle progression that exists in two distinct isoforms, cyclin D1a and D1b. In the prostate, cyclin D1a acts through discrete mechanisms to negatively regulate androgen receptor (AR) activity and thus limit androgen-dependent proliferation. Accordingly, cyclin D1a is rarely overexpressed in prostatic adenocarcinoma and holds little prognostic value in this tumor type. However, a common polymorphism (A870) known to facilitate production of cyclin D1b is associated with increased prostate cancer risk. Here we show that cyclin D1b is expressed at high frequency in prostate cancer and is up-regulated in neoplastic disease. Furthermore, our data demonstrate that, although cyclin D1b retains AR association, it is selectively compromised for AR regulation. The altered ability of cyclin D1b to regulate the AR was observed by using both in vitro and in vivo assays and was associated with compromised regulation of AR-dependent proliferation. Consistent with previous reports, expression of cyclin D1a inhibited cell-cycle progression in AR-dependent prostate cancer cells. Strikingly, cyclin D1b significantly stimulated proliferation in this cell type. AR-negative prostate cancer cells were nonresponsive to cyclin D1 (a or b) expression, indicating that defects in AR corepressor function yield a growth advantage specifically in AR-dependent cells. In summary, these studies indicate that the altered AR regulatory capacity of cyclin D1b contributes to its association with increased prostate cancer risk and provide evidence of cyclin D1b-mediated transcriptional regulation.

Original languageEnglish (US)
Pages (from-to)2190-2195
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number7
DOIs
StatePublished - Feb 14 2006

Keywords

  • Cell cycle
  • Corepressor
  • G870A
  • Polymorphism
  • Thyroid hormone receptor β

ASJC Scopus subject areas

  • General

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  • Cite this

    Burd, C. J., Petre, C. E., Morey, L. M., Wang, Y., Revelo, M. P., Haiman, C. A., Lu, S., Fenoglio-Preiser, C. M., Li, J., Knudsen, E. S., Wong, J., & Knudsen, K. E. (2006). Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proceedings of the National Academy of Sciences of the United States of America, 103(7), 2190-2195. https://doi.org/10.1073/pnas.0506281103