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Objective: To investigate the function and causative role of simvastatin (Sim) in breast carcinoma cell apoptosis as well as proliferation. Methods: 20 breast carcinoma patients requiring surgery were treated with Sim (20 days, 30 mg), and samples of pre-treatment (pre) and post-treatment (post) were acquired. We detected tissue cell proliferation and apoptosis changes and used functional experiments to detect cell proliferation and apoptosis changes after treating not only estrogen receptor (ER)-positive (MCF-7) but also ER-negative cells (MDA-MB-231) with Sim or TGF-β1. Detection of p-Smad3 and total Smad3 protein expression changes was conducted, and we finally used in vivo experiments to assess the influence of Sim on breast tumor growth and drug safety. Results: Immunohistochemistry and TUNEL staining results showed that after treatment with Sim, breast carcinoma cell proliferation decreased and apoptosis increased. Functional experiments results showed that Sim notedly promoted the MDA-MB-231 and MCF-7 cell apoptosis, inhibiting migration, proliferation and epithelial mesenchymal transition. Moreover, TGF-β1 protein expression was strikingly lower in Sim group than that in DMSO group. When TGF-β1 and Sim were combined to use, the inhibitory ability of Sim on breast cancer cell proliferation markedly increased and the capability of TGF-β1 protein inducing p-Smad3 protein increased. In addition, after Sim treatment in mice, the tumor volume became smaller, the pathological changes weakened, and there was no significant effect on liver function and kidney function. Conclusion: Sim participates in breast cancer cell apoptosis and proliferation via regulating TGF-β1/Smad3 signal pathway.

Olaparib has been used in the treatment of triple-negative breast cancer (TNBC) with BRCA mutations. In the present study, we demonstrated the effect of miR-27-3p on the γ-secretase pathway by regulating the sensitivity of TNBC cells to olaparib. miR-27-3p, a microRNA with the potential to target PSEN-1, the catalytic subunit of γ-secretase mediating the second step of the cleavage of the Notch protein, was identified by the online tool miRDB and found to inhibit the expression of PSEN-1 by directly targeting the 3’-untranslated region (3’-UTR) of PSEN-1. The overexpression of miR-27-3p inhibited the activation of the Notch pathway via the inhibition of the cleavage of the Notch protein, mediated by γ-secretase, and, in turn, enhanced the sensitivity of TNBC cells to the antitumor agent olaparib. Transfection with PSEN-1 containing mutated targeting sites for miR-27-3p or the expression vector of the Notch protein intracellular domain (NICD) almost completely blocked the effect of miR-27-3p on the Notch pathway or the sensitivity of TNBC cells to olaparib, respectively. Therefore, our results suggest that the miR-27-3p/γ-secretase axis participates in the regulation of TNBC and that the overexpression of miR-27-3p represents a potential approach to enhancing the sensitivity of TNBC to olaparib.

Murrayanine and its derivatives have been shown to exhibit anticancer activities against different types of human cancer cells. However, the effects of murrayanine on the proliferation and metastasis of breast cancer cells are yet to be studied. The present study was designed to evaluate the effects of murrayanine on the proliferation and metastasis of human breast cancer via regulation of RANK/RANKL pathway. The results showed RANK/RANKL pathway to be highly activated in human breast cancer tissues and cell lines. However, treatment of the CAMA-1 breast cancer cells with murrayanine (0, 9, 18 and 36 μM) caused a significant (P 50of 18 μM. The antiproliferative of murrayanine were found be due to its ability to inhibit the expression of RANK, RANKL and OPG in CAMA-1 cells. To unveil if murrayanine exerted its effects via inhibition of RANK/RANKL pathway, the expression of RNAK was knocked down in CAMA-1 cells. It was found that murrayanine and RANK silencing both inhibited the growth CAMA-1 cells via induction of apoptosis. Additionally, murrayanine and RANK silencing both inhibited the migration, invasion and epithelial to mesenchymal transition of the CAMA-1 cells. Taken together, murrayanine exhibits significant anticancer activity against the breast cancer cells via induction of apoptosis and inhibition of RANK/RANKL signaling pathway. These findings suggest that murrayanine may prove to be a beneficial lead molecule for the development of breast cancer chemotherapy.

Background Breast cancer is the most common malignant tumor in women worldwide, with a high mortality rate. MicroRNAs are small non-coding RNAs that negatively regulate the expression of target genes by interacting with the target gene 3'-UTR, and participate in cell differentiation, proliferation, apoptosis and metabolism. The function of miRNA-96-5p in the progression of breast cancer has not been reported. Methods We used the StarBase database to investigate the expression of miRNA-96-5p in breast cancer and adjacent normal tissues. FOXO3 3'-UTR construct and luciferase reporter assays was performed for the target gene. Expression levels of miRNAs including its target were analyzed by qRT-PCR and western blot. Cell proliferation was detected by CCK8 and colony formation, EdU assay. Results Luciferase reporter assays showed miRNA-96-5p directly targeted FOXO3. Abrogation of miRNA-96-5p by transfection with its inhibitors in breast cancer cells significantly suppressed miRNA-96-5p expression and breast cancer cells proliferation. Western blot revealed that overexpression of miRNA-96-5p substantially reduced FOXO3 protein expression. We used the GEPIA, UALCAN and KM-plotter databases to investigate the expression of FOXO3 in human breast cancer and adjacent normal tissues, and its correlation with survival. In addition, we found that FOXO3 spoiled miR-96-5p induced breast cancer cell proliferation block effecting. Conclusions miRNA-96-5p may exert a tumor promotion role through negatively regulating tumor suppressor gene FOXO3 and promoting cell proliferation.