Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators.

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. The epithelial-to-mesenchymal transition (EMT) is a key contributor in the metastatic process. We previously showed the pan-deacetylase inhibitor LBH589 induces CDH1 expression in TNBC cells, suggesting regulation of EMT. The purpose of this study was to examine the effects of LBH589 on the metastatic qualities of TNBC cells and the role of EMT in this process. A panel of breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549), drugged with LBH589, was examined for changes in cell morphology, migration, and invasion in vitro. The effect on in vivo metastasis was examined using immunofluorescent staining of lung sections. EMT gene expression profiling was used to determine LBH589-induced changes in TNBC cells. ZEB overexpression studies were conducted to validate requirement of ZEB in LBH589-mediated proliferation and tumorigenesis. Our results indicate a reversal of EMT by LBH589 as demonstrated by altered morphology and altered gene expression in TNBC. LBH589 was shown to be a more potent inhibitor of EMT than other HDAC inhibitors, SAHA and TMP269. Additionally, we found that LBH589 inhibits metastasis of MDA-MB-231 cells in vivo. These effects of LBH589 were mediated in part by inhibition of ZEB, as overexpression of ZEB1 or ZEB2 mitigated the effects of LBH589 on MDA-MB-231 EMT-associated gene expression, migration, invasion, CDH1 expression, and tumorigenesis. These data indicate therapeutic potential of LBH589 in targeting EMT and metastasis of TNBC.

• Authors: Lyndsay V Rhodes, Chandra R Tate, H Chris Segar, Hope E Burks, Theresa B Phamduy, Van Hoang, Steven Elliott, Diari Gilliam, F Nell Pounder, Muralidharan Anbalagan, Douglas B Chrisey, Brian G Rowan, Matthew E Burow, Bridgette M Collins-Burow
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 145 Issue 3 Pg. 593-604 (Jun 2014) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 24810497 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Homeodomain Proteins
• Hydroxamic Acids
• Indoles
• Repressor Proteins
• Transcription Factors
• ZEB1 protein, human
• ZEB2 protein, human
• Zinc Finger E-box Binding Homeobox 2
• Zinc Finger E-box-Binding Homeobox 1
• Panobinostat

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast (pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Homeodomain Proteins (antagonists & inhibitors, biosynthesis)
• Humans
• Hydroxamic Acids (pharmacology)
• Indoles (pharmacology)
• MCF-7 Cells
• Mice
• Mice, SCID
• Neoplasm Invasiveness (pathology)
• Neoplasm Metastasis (drug therapy)
• Panobinostat
• Repressor Proteins (antagonists & inhibitors, biosynthesis)
• Transcription Factors (antagonists & inhibitors, biosynthesis)
• Triple Negative Breast Neoplasms (drug therapy)
• Xenograft Model Antitumor Assays
• Zinc Finger E-box Binding Homeobox 2
• Zinc Finger E-box-Binding Homeobox 1