BackgroundIncreased expression of voltage-gated sodium channels (VGSCs) have been implicated with strong metastatic potential of human breast cancer in vitro and in vivo where the main culprits are cardiac isoform Nav1.5 and its ‘neonatal’ splice variant, nNav1.5. Several factors have been associated with Nav1.5 and nNav1.5 gain of expression in breast cancer mainly hormones, and growth factors.AimThis study aimed to investigate the role of epigenetics via transcription repressor, repressor element silencing transcription factor (REST) and histone deacetylases (HDACs) in enhancing Nav1.5 and nNav1.5 expression in human breast cancer by assessing the effect of HDAC inhibitor, trichostatin A (TSA).MethodsThe less aggressive human breast cancer cell line, MCF-7 cells which lack Nav1.5 and nNav1.5 expression was treated with TSA at a concentration range 10–10,000 ng/ml for 24 h whilst the aggressive MDA-MB-231 cells was used as control. The effect of TSA on Nav1.5, nNav1.5, REST, HDAC1, HDAC2, HDAC3, MMP2 and N-cadherin gene expression level was analysed by real-time PCR. Cell growth (MTT assay) and metastatic behaviors (lateral motility and migration assays) were also measured.ResultsmRNA expression level of Nav1.5 and nNav1.5 were initially very low in MCF-7 compared to MDA-MB-231 cells. Inversely, mRNA expression level of REST, HDAC1, HDAC2, and HDAC3 were all greater in MCF-7 compared to MDA-MB-231 cells. Treatment with TSA significantly increased the mRNA expression level of Nav1.5 and nNav1.5 in MCF-7 cells. On the contrary, TSA significantly reduced the mRNA expression level of REST and HDAC2 in this cell line. Remarkably, despite cell growth inhibition by TSA, motility and migration of MCF-7 cells were enhanced after TSA treatment, confirmed with the up-regulation of metastatic markers, MMP2 and N-cadherin.ConclusionsThis study identified epigenetics as another factor that regulate the expression level of Nav1.5 and nNav1.5 in breast cancer where REST and HDAC2 play important role as epigenetic regulators that when lacking enhances the expression of Nav1.5 and nNav1.5 thus promotes motility and migration of breast cancer. Elucidation of the regulatory mechanisms for gain of Nav1.5 and nNav1.5 expression may be helpful for seeking effective strategies for the management of metastatic diseases.

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Background: Back ground: The wide use of Neoadjuvant chemotherapy nowadays became so wide to the degree that it is more or less established as a standard regimen in management of breast neoplasia, in spite of different outcome results. Expression of epithelial cell adhesion molecule (EpCAM) is deregulated in epithelial malignancies. It is found that it acts as signaling molecule with tumor-promoting functions in addition to its role in cell adhesion. Aim of Work: It is aimed to assess the expression intensity of malignant mammary cells of EpCAM and its relation to the patient out come and their response to neoadjuvant chemotherapy. Methods: 140 patients with breast carcinoma and undergone treatment with neoadjuvant chemotherapy were included in the study. Both Tru-cut tissue biopsy and radically-excised breast tissues; before and after neoadjuvant chemotherapy, were examined for intensity of staining by EpCAM. Results: High intensity of EpCAM expression pattern is found correlated with lymphovascular invasion status and higher nuclear grade (P ¼ 0.01 and 0.008, respectively), and was associated with poor outcome (P < 0.001). We also found that patients with high EpCAM expression before and after neoadjuvant chemotherapy showed worse pathological and clinical outcome (P ¼ 0.008 and <0.001, respectively) than the patients with high intensity before and low intensity after neoadjuvant chemotherapy. The overall survival rate of the first group is less than the second one (P ¼ 0.049).