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

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 (ER)-positive breast cancer cell lines are up to 10 times more sensitive than ER-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-positive MCF-7 cell line, TSA repressed ER 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-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-mediated cyclin D1 transcription, and acquired resistance to tamoxifen is associated with a shift to ER-independent cyclin D1 up-regulation. Taken together, our data show that TSA effectively induces cyclin D1 down-regulation through both ER-dependent and ER-independent mechanisms, providing an important new strategy for combating resistance to antiestrogens.

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