Bortezomib enhances the efficacy of fulvestrant by amplifying the aggregation of the estrogen receptor, which leads to a proapoptotic unfolded protein response

Yuki Ishii, Luena Papa, Urvashi Bahadur, Zhenyu Yue, Julio Aguirre-Ghiso, Toshi Shioda, Samuel Waxman, Doris Germain

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Purpose: Fulvestrant is known to promote the degradation of the estrogen receptor (ER) in the nucleus. However, fulvestrant also promotes the aggregation of the newly synthesized ER in the cytoplasm. Accumulation of protein aggregates leads to cell death but this effect is limited as a result of their elimination by the proteasome. We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death. Experimental Design: The rate of aggregation of the ER was monitored in ER+ breast cancer cells lines, T47D, ZR-75.1, BT474, MDA-MB-361, MCF-7, fulvestrant resistance MCF-7, and tamoxifen-resistant T47D-cyclin D1 cells. Activation of the unfolded protein response, apoptosis, and metabolic rate were also monitored in these cell lines following treatment with fulvestrant, bortezomib, or bortezomib in combination with fulvestrant. Results: We found that bortezomib enhances the fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking the degradation of the ER in the nucleus. Further, these aggregates activate a sustained unfolded protein response leading to apoptotic cell death. Further, we show that the combination induced tumor regression in a breast cancer mouse model of tamoxifen resistance. Conclusions: Adding bortezomib to fulvestrant enhances its efficacy by taking advantage of the unique ability of fulvestrant to promote cytoplasmic aggregates of the ER. As this effect of fulvestrant is independent of the transcriptional activity of the ER, these results suggest that this novel combination may be effective in breast cancers that are ER + but estrogen independent.

Original languageEnglish (US)
Pages (from-to)2292-2300
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
StatePublished - Apr 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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