Open AccessBET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine
Author(s) -
Deepak Kanojia,
Wojciech K. Panek,
Álex 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
Publication year - 2020
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aax2879
Subject(s) - vinorelbine , metastatic breast cancer , breast cancer , cancer research , medicine , brain metastasis , paclitaxel , cancer , oncology , pharmacology , metastasis , chemotherapy , cisplatin
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.