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Aberrant expression or function of epidermal growth factor receptor (EGFR) or the closely related human epidermal growth factor receptor 2 (HER2) can promote cell proliferation and survival, thereby contributing to tumorigenesis. Specific antibodies and low-molecular-weight tyrosine kinase inhibitors of both proteins are currently in clinical trials for cancer treatment. Benzimidazole derivatives possess diverse biological activities, including antitumor activity. However, the anticancer mechanism of 5a (a 2-aryl benzimidazole compound; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C16H14ClN3O, MW299), a novel 2-aryl benzimidazole derivative, toward breast cancer is largely unknown. Here, we demonstrate that 5a potently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosine phosphorylation and preventing downstream activation of PI3K/Akt and MEK/Erk pathways in vitro and in vivo. We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis. Moreover, 5a potently induced apoptosis via the c-Jun N-terminal kinase (JNK)-mediated death receptor 5 upregulation in breast cancer cells. The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo. Analysis of the primary breast cancer cell lines with HER2 overexpression further confirmed that 5a significantly inhibited Akt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.

Serum circulating microRNAs (c‐miRNAs) are serving as useful biomarkers for cancer diagnosis. Here, we describe the development of a one‐step branched rolling circle amplification (BRCA) method to measure serum c‐miRNAs levels for early diagnosis of breast cancer. Four c‐miRNAs, c‐miRNA16 (c‐miR‐16), c‐miRNA21 (c‐miR‐21), c‐miRNA155 (c‐miR‐155), and c‐miRNA195 (c‐miR‐195) were isolated from the serum of 49 breast cancer patients (stages I‐IV) and 19 healthy controls, and analyzed using one‐step BRCA. The serum levels of c‐miR16, c‐miR21, c‐miR155, and c‐miR195 were higher (P < 0.0001) in stage I breast cancer patients than healthy controls. These levels were also higher in several breast cancer molecular subtypes (HER‐2 over‐expression, Luminal A, Luminal B, and triple negative breast cancer) than in healthy control subjects. The diagnostic accuracy of c‐miR16, c‐miR21, c‐miR155, and c‐miR195 for early diagnosis of breast cancer was confirmed by receiver operating characteristic (ROC) curve assay. These results show that the BRCA method can be used to measure serum c‐miRNAs levels, and that this method has high accuracy, sensitivity, and specificity. Moreover, both BRCA approach and quantitative real‐time PCR (qRT‐PCR) method show that the serum levels of c‐miR16, c‐miR21, c‐miR155, and c‐miR195 could be used as biomarkers to improve the early diagnosis of breast cancer, and distinguish different breast cancer molecular subtypes.

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The results of this study bode well for the application of CORM-3 as an anti-inflammatory agent to inhibit NF-κB activity and to suppress the expression of adhesion molecules on HGF, which suggests a promising potential for CORM-3 in the treatment of inflammatory periodontal disease.