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Proteasome inhibition represses ERα gene expression in ER+ cells: a new link between proteasome activity and estrogen signaling in breast cancer

Oncogene volume 29, pages 1509–1518 (2010)Cite this article

Abstract

Estrogen receptor-α (ERα) is a major therapeutic target of hormonal therapies in breast cancer, and its expression in tumors is predictive of clinical response. Protein levels of ERα are tightly controlled by the 26S proteasome; yet, how the clinical proteasome inhibitor, bortezomib, affects ERα regulation has not been studied. Bortezomib selectively inhibits the chymotrypsin-like activity of the proteasome. Unlike other laboratory proteasome inhibitors, bortezomib failed to stabilize ERα protein at a dose exceeding 90% inhibition of the chymotrypsin-like activity. Unexpectedly, however, chronic bortezomib exposure caused a reduction of ERα levels in multiple ER+ breast cancer cell lines. This response can be explained by the fact that bortezomib induced a dramatic decrease in ERα mRNA because of direct transcriptional inhibition and loss of RNA polymerase II recruitment on the ERα gene promoter. Bortezomib treatment resulted in promoter-specific changes in estrogen-induced gene transcription that related with occupancy of ERα and RNA polymerase II (PolII) on endogenous promoters. In addition, bortezomib inhibited estrogen-dependent growth in soft agar. These results reveal a novel link between proteasome activity and expression of ERα in breast cancer and uncover distinct roles of the chymotrypsin-like activity of the proteasome in the regulation of the ERα pathway.

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Acknowledgements

This work was supported by Grants NIH DK64034 (ETA), DAMD-17-02-1-0286 (AVL), T32CA009135 (GLP), T32GM08688 (GLP) and W81XWH-06-1-0714 (AJC). We thank Drs Shigeki Miyamoto and Michael Fritsch for reagents.

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  1. Department of Oncology, University of Wisconsin-Madison, Madison, WI, USA

    G L Powers, S J Ellison-Zelski & E T Alarid

  2. Lester and Sue Smith Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    A J Casa & A V Lee

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Correspondence to E T Alarid.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Powers, G., Ellison-Zelski, S., Casa, A. et al. Proteasome inhibition represses ERα gene expression in ER+ cells: a new link between proteasome activity and estrogen signaling in breast cancer. Oncogene 29, 1509–1518 (2010). https://doi.org/10.1038/onc.2009.434

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