Efforts to induce the differentiation of cancer stem cells through treatment with all-trans retinoic acid (ATRA) have yielded limited success, partially due to the epigenetic silencing of the retinoic acid receptor (RAR)-β. The histone deacetylase inhibitor, entinostat, is emerging as a promising antitumor agent when added to the standard of care treatment for breast cancer. However, the combination of epigenetic, cellular differentiation, and chemotherapeutic approaches against triple negative breast cancer (TNBC) has not been investigated. In this study, we found that combined treatment of TNBC xenografts with entinostat, ATRA, and doxorubicin (EAD) resulted in significant tumor regression and restoration of epigenetically silenced RAR-β expression. Entinostat and doxorubicin treatment inhibited topoisomerase II-β (Topo II-β) and relieved Topo II-β-mediated transcriptional silencing of RAR-β. Notably, EAD was the most effective combination in inducing differentiation of breast tumor-initiating cell in vivo. Furthermore, gene expression analysis revealed that the epithelium-specific ETS transcription factor-1 (ESE-1 or ELF3), known to regulate proliferation and differentiation, enhanced cell differentiation in response to EAD triple therapy. Finally, we demonstrate that patient-derived metastatic cells also responded to treatment with EAD. Collectively, our findings strongly suggest that entinostat potentiates doxorubicin-mediated cytotoxicity and retinoid-driven differentiation to achieve significant tumor regression in TNBC.

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Introduction: Soft tissue sarcomas comprise a heterogeneous group of clinically aggressive cancers that are often hard to classify on limited cytological samples. Results: The common morphological denominators for most translocation sarcomas were: hypercellularity, cellular monotony, mostly discohesive and single cells, roundto-oval or short spindled cells and a lack of necrosis. The exceptions were an inflammatory myofibroblastic tumour, in which cellular monotony was not present owing to the prominence of lymphocytes and plasma cells, and low-grade fibromyxoid sarcoma, in which the specimens were generally hypocellular. Ancillary testing, especially immunoperoxidase staining, was often required for primary lesions.Conclusion: Distinct morphological clues and subsequent ancillary testing (particularly immunoperoxidase staining) provide an accurate diagnosis on cytological interpretation of both, primary and recurrent/metastatic lesions. In the present, a series of 147 TS collected over a 25-year period (n=130) and exfoliative cytology (n=17) specimens. | RESULTSThe 147 translocation sarcoma cases that were included in this review had a wide patient age range of 15 months to 86 years (Table 1). There was a slight male predominance of 1.2:1. The most common primary anatomic site was soft tissues (n=96), especially the lower extremity (n=41) and the chest/ abdomen (n=22), followed by metastatic lesions in the lung (n=18).The exfoliative samples consisted predominantly of serous cavity effusions (n=13) and two each of cerebrospinal fluid and bronchoscopic washing specimens.During the review of each case, it was noted whether the tumours were primary, recurrent or metastatic at the time of diagnosis (Table 2). Of the 147 cases, 71 were primary, 24 were recurrent, and 52 were metastatic. There were 28 EWS primaries, all of which were definitively diagnosed using a combination of cytomorphology, IPOX, EM (two cases) and cytogenetic studies (five cases). Of the 14 SS primary tumours, eight were definitively diagnosed as SS by cytomorphology and IPOX, whereas six were called spindle cell neoplasm and diagnosed by histology and IPOX on subsequent core biopsy material. All of the primary DSRCT and CCS cases were originally diagnosed as those entities by cytomorphology and IPOX; all primary MLS cases were definitively diagnosed on cytomorphology in conjunction with cell block and/or core biopsy material. The single ASPS specimen had corresponding core biopsies taken at the time of FNA which aided in the diagnosis of ASPS. None of the four primary EMC cases were originally diagnosed as EMC. The four EMC diagnoses were: spindle cell neoplasm with chondromyxoid differentiation; mesenchymal neoplasm with chondromyxoid features; spindle cell neoplasm with myxoid features; and malignant myxoid neoplasm.