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Clinical Cancer Research Vol. 10, 8094-8104, December 1, 2004
© 2004 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Histone Deacetylase Inhibitor Trichostatin A Represses Estrogen Receptor {alpha}-Dependent Transcription and Promotes Proteasomal Degradation of Cyclin D1 in Human Breast Carcinoma Cell Lines

John Patrick Alao1, Eric W-F. Lam1, Simak Ali1, Laki Buluwela1, Walter Bordogna2, Peter Lockey2, Rana Varshochi1, Alexandra V. Stavropoulou1, R. Charles Coombes1 and David M. Vigushin1

1 Department of Cancer Medicine, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; and 2 Argenta Discovery Ltd., Harlow, United Kingdom

Purpose: Estrogen receptor {alpha} (ER{alpha})-positive breast cancer cell lines are up to 10 times more sensitive than ER{alpha}-negative cell lines to the antiproliferative activity of the histone deacetylase inhibitor trichostatin A (TSA). The purpose of the study was to investigate the mechanisms underlying this differential response.

Experimental Design and Results: In the ER{alpha}-positive MCF-7 cell line, TSA repressed ER{alpha} and cyclin D1 transcription and induced ubiquitin dependent proteasomal degradation of cyclin D1, leading primarily to G1-S-phase cell cycle arrest. By contrast, cyclin D1 degradation was enhanced but its transcription unaffected by TSA in the ER{alpha}-negative MDA-MB-231 cell line, which arrested in G2-M phase. Cyclin D1 degradation involved Skp2/p45, a regulatory component of the Skp1/Cullin/F-box complex; silencing SKP2 gene expression by RNA interference stabilized cyclin D1 and abrogated the cyclin D1 down-regulation response to TSA.

Conclusions: Tamoxifen has been shown to inhibit ER{alpha}-mediated cyclin D1 transcription, and acquired resistance to tamoxifen is associated with a shift to ER{alpha}-independent cyclin D1 up-regulation. Taken together, our data show that TSA effectively induces cyclin D1 down-regulation through both ER{alpha}-dependent and ER{alpha}-independent mechanisms, providing an important new strategy for combating resistance to antiestrogens.




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Copyright © 2004 by the American Association for Cancer Research.