Received for publication January 19, 2007.
Revised March 28, 2007.
Accepted for publication March 28, 2007.

Proteasome Regulated ERBB2 and Estrogen Receptor Pathways in Breast Cancer

Abstract

A major challenge to broadening oncology applications for inhibitors of the ubiquitin-proteasome system (UPS) is the identification of UPS-dependent cancer pathways predictive of tumors responsive to peptidomimetic inhibitors of its 20S core protease activity. To inform clinical studies evaluating UPS inhibitors as breast cancer therapeutics, seven phenotypically diverse human breast cancer cell line models were characterized for their cellular and molecular responses to the clinically approved 20S inhibitor, bortezomib (PS341, Velcade), focusing on those overexpressing estrogen receptor (ER) or ERBB2/HER2, as these oncogenic receptor pathways are constitutively activated in ~80% of all breast cancers. All models demonstrated dose-dependent bortezomib reduction in intracellular 20S activity correlating with cell growth inhibition; and bortezomib IC₅₀ values (concentrations producing 50% growth inhibition) varied directly with pretreatment 20S activities (r = 0.74, p<0.05), suggesting that basal 20S activity may serve as a clinical predictor of tumor responsiveness to UPS inhibition. Reduction in 20S activity (> 60%) was associated with early (24 h) intracellular relocalization of ER (nucleus to cytoplasm) and ERBB2 (plasma membrane to perinuclear lysosomes), buildup of ubiquitinated and Hsp70-associated receptor, degradation and loss of ER and ERBB2 function, and induction of cellular apoptosis. These models were also used to screen a pharmacologic panel of pathway-targeted anticancer agents (AG825, AZD6244/ARRY142886, LY294002, 17AAG, LAQ824) for those capable of sensitizing to bortezomib. In keeping with the observation that 20S reduction has little effect on MEK1/2 signaling in either ER-positive or ERBB2-positive models, only the MEK1/2 inhibitor AZD6244 consistently improved the antitumor activity of bortezomib.

Key words: Mechanisms of cell killing/apoptosis, Membrane targets

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