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 language | English (US) |
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Article number | eaax2879 |
Journal | Science translational medicine |
Volume | 12 |
Issue number | 558 |
DOIs | |
State | Published - Aug 2020 |
Funding
We would like to thank A. Lopez-Rosas for technical assistance. We thank D. Horiuchi for cell lines and V5-tagged antibody. We thank E. Gonzalez-Buendia for assistance with ChIP analysis and J. R. Kane for critically reading the manuscript. We would like to thank J. Massague (MSKCC) for providing the MDA-MB-231Br, CN34, and CN34Br cell lines. We would like to thank D. Yu (MD Anderson Cancer Centre) for providing the BT-474 and BT-474Br cell lines. This work was supported by NIH grants R35CA197725, R01NS093903, and P50CA221747 to M.S.L., R01NS87990 to M.S.L. and I.V.B., R01NS106379 01A1 to I.V.B., 1R01NS096376-01A1 to A.U.A., 5R21CA220625 to K.K., and R01NS102669 to C.H. Author
ASJC Scopus subject areas
- General Medicine