Abstract
Claudin-low triple negative breast cancer (CL-TNBC) is a clinically aggressive molecular TNBC subtype characterized by a propensity to metastasize, recur and acquire chemoresistance. CL-TNBC has a diverse intra- and extracellular composition and microenvironment, and currently there are no clinically approved targeted therapies. Histone deacetylase inhibitors (HDACi) have been investigated as therapeutic agents targeting invasive TNBC phenotypes. However, further studies are required to evaluate HDAC inhibition in CL-TNBC. Here, we utilize a novel CL- TNBC patient-derived xenograft model to study the various and diverse therapeutic potential targets within CL-TNBC tumors. To evaluate effects of the pan-HDACi panobinostat on metastasis and the mesenchymal phenotype of CL-TNBC, we utilize immunohistochemistry staining and qRT-PCR in in vitro, ex vivo and in vivo studies. Further, we evaluate pan-HDAC inhibition on stem-like subpopulations using 3D mammosphere culture techniques and quantification. Finally, we show that pan- HDACi suppresses collagen expression in CL-TNBC. In this study, we provide evidence that pan-HDAC inhibition has effects on various components of the CL-TNBC subtype, and we demonstrate the potential of our novel CL-TNBC PDX model in therapeutic discovery research.
Highlights
Triple negative breast cancers (TNBCs) constitute approximately 12% of all breast cancers; TNBCs have a poorer short-term prognosis than other breast cancer subtypes [1]
We demonstrate the value of using translational patientderived xenograft (PDX) models in target discovery and therapeutic research, especially in clinically aggressive TNBC tumors such as the claudin-low TNBC subtype
We observed that treatment of various TNBC PDX explants, established in our laboratory, with LBH59 has similar gene expression changes that are characteristic of mesenchymal phenotype reversal
Summary
Triple negative breast cancers (TNBCs) constitute approximately 12% of all breast cancers; TNBCs have a poorer short-term prognosis than other breast cancer subtypes [1]. HDAC inhibitors have biological effects in multiple cancer pathways, including proliferation, migration, angiogenesis and immune response [25] For this reason, they have potential for targeting many individual components that comprise the complex CL-TNBC subtype, including targeting the mesenchymal phenotype, the cancer stem cell (CSC) population and extracellular matrix (ECM) components. We evaluated if the effect of LBH589, a pan-DACi, had similar genomic changes after treatment of intact PDX tumors compared to our findings with treated cell lines. We examined mRNA expression changes in the tumors removed at the termination of the experiment and found that, as observed in our ex vivo experiment and in cell lines, treatment with LBH589 increases CDH1 and significantly suppressed VIM and ZEB2 mRNA expression (Figure 2B). COL1A1 gene expression changes were not significant in either MDA-MB-231 nor TU-BcX-2O0 cells
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