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

Estrogen receptor-alpha (ER alpha) is a major therapeutic target of hormonal therapies in breast cancer, and its expression in tumors is predictive of clinical response. Protein levels of ER alpha are tightly controlled by the 26S proteasome; yet, how the clinical proteasome inhibitor, bortezomib, affects ER alpha regulation has not been studied. Bortezomib selectively inhibits the chymotrypsin-like activity of the proteasome. Unlike other laboratory proteasome inhibitors, bortezomib failed to stabilize ER alpha protein at a dose exceeding 90% inhibition of the chymotrypsin-like activity. Unexpectedly, however, chronic bortezomib exposure caused a reduction of ER alpha levels in multiple ER+ breast cancer cell lines. This response can be explained by the fact that bortezomib induced a dramatic decrease in ER alpha mRNA because of direct transcriptional inhibition and loss of RNA polymerase II recruitment on the ER alpha gene promoter. Bortezomib treatment resulted in promoter-specific changes in estrogen-induced gene transcription that related with occupancy of ER alpha 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 ER alpha in breast cancer and uncover distinct roles of the chymotrypsin-like activity of the proteasome in the regulation of the ER alpha pathway. Oncogene (2010) 29, 1509-1518; doi:10.1038/onc.2009.434; published online 30 November 2009