BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine

Deepak Kanojia, Wojciech K. Panek, Alex Cordero, Jawad Fares, Annie Xiao, Solomiia Savchuk, Krishan Kumar, Ting Xiao, Katarzyna C. Pituch, Jason Miska, Peng Zhang, Kwok Ling Kam, Craig Horbinski, Irina V. Balyasnikova, Atique U. Ahmed, Maciej S. Lesniak*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Metastases from primary breast cancer result in poor survival. βIII-tubulin (TUBB3) has been established as a therapeutic target for breast cancer metastases specifically to the brain. In this study, we conducted a systematic analysis to determine the regulation of TUBB3 expression in breast cancer metastases to the brain and strategically target these metastases using vinorelbine (VRB), a drug approved by the U.S. Food and Drug Administration (FDA). We found that human epidermal growth factor receptor 2 (HER2) signaling regulates TUBB3 expression in both trastuzumab-sensitive and trastuzumab-resistant neoplastic cells. We further discovered that bromodomain and extra-terminal domain (BET) inhibition increases TUBB3 expression, rendering neoplastic cells more susceptible to apoptosis by VRB. Orthotopic xenograft assays using two different breast cancer cell models revealed a reduction in tumor volume with BET inhibition and VRB treatment. In addition, in vivo studies using a model of multiple brain metastasis (BM) showed improved survival with the combination of radiation + BET inhibitor (iBET-762) + VRB (75% long-term survivors, P < 0.05). Using in silico analysis and BET inhibition, we found that the transcription factor myeloid zinc finger-1 (MZF-1) protein binds to the TUBB3 promoter. BET inhibition decreases MZF-1 expression and subsequently increases TUBB3 expression. Overexpression of MZF-1 decreases TUBB3 expression and reduces BM in vivo, whereas its knockdown increases TUBB3 expression in breast cancer cells. In summary, this study demonstrates a regulatory mechanism of TUBB3 and provides support for an application of BET inhibition to sensitize breast cancer metastases to VRB-mediated therapy.

Original languageEnglish (US)
Article numbereaax2879
JournalScience translational medicine
Volume12
Issue number558
DOIs
StatePublished - Aug 2020

ASJC Scopus subject areas

  • Medicine(all)

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