Malignant Triple-negative Breast Cancer Research Articles

Repurposing maduramicin as a novel anticancer and anti-metastasis agent for triple-negative breast cancer as enhanced by nanoemulsion

Triple-negative breast cancer (TNBC) is featured by aggression and metastasis and remains an unmet medical challenge due to high death rate. We aimed to repurpose maduramicin (MAD) as an effective drug against TNBC, and develop a nanoemulsion system to enhance anticancer efficacy of MAD. MDA-MB-231 and 4 T1 cells were used as in vitro model, and cell viability was determined by performing cell counting kit-8 and a colony-formation assay. Furthermore, MAD loaded nanoemulsion (MAD-NEs) was manufactured and characterized by a series of tests. The anticancer and anti-metastasis mechanism of MAD-NEs were assessed by performing cell cycle, apoptosis, wound-healing, transwell assay and Western blotting assays. Herein, MAD was firstly demonstrated to be an effective agent to suppress growth of TNBC cells. Subsequently, the optimized MAD-NEs were shown to have stability and high encapsulation efficiency, and could arrested cells in G0/G1 phase and induced apoptosis in TNBC cells. More importantly, MAD-NEs significantly impeded the metastasis of tumor cells, which was further demonstrated by the significant altered expression of epithelial-mesenchymal transition and extracellular matrix markers in vitro and in vivo. Moreover, compared to MAD, MAD-NEs exhibited higher efficacy in shrinking breast tumor size and repressing liver and lung metastasis in vivo, and showed excellent biocompatibility in tumor-bearing mice. The successfully prepared MAD-NEs are expected to be harnessed to suppress tumor growth, invasion and metastasis in the battle against malignant TNBC.

PIBF1 suppresses the ATR/CHK1 signaling pathway and promotes proliferation and motility of triple-negative breast cancer cells

This study evaluates the oncogenic role of PIBF1 in triple-negative breast cancer (TNBC). TNBC is considered to have a poorer prognosis than other types of breast cancer and is associated with high risk of recurrence and distant metastasis. Currently, there are no effective therapies for the TNBC patients with distant metastasis due to the lack of targeted therapeutic options. The effects of PIBF1 knockdown on the cell viability and motility of TNBC cell lines were investigated. Effects of PIBF1 overexpression on tumorigenicity and cell motility were confirmed using Ba/F3 cell line and xenograft study on BALB/c nude mice. In TNBC cell lines that highly express PIBF1, knockdown of PIBF1 induces apoptosis and suppresses cell viability and motility with activation of the ATR/CHK1 signaling pathway. Moreover, the oncogenic function of PIBF1 was confirmed using the Ba/F3 cell line. For the first time, these findings clarify the role of PIBF1 in regulating ATR/CHK1 signaling pathway and inhibiting the proliferation and migration of TNBC cell lines. These results demonstrate the oncogenic roles of PIBF1 and provide new insights into the function and the molecular mechanism of PIBF1 in malignant TNBC.

From solid state to in vitro anticancer activity of copper(II) compounds with electronically-modulated NNO Schiff base ligands.

The copper(ii) complexes of general formula [Cu(GL)(Cl)] (1-3, G = OMe, H and NO2, respectively), bearing tridentate Schiff base ligands (GL-) and a chloride as a fourth labile one, are here reported. The Schiff bases derive from the monocondensation of ethylenediamine and substituted salicylaldehyde, where the electronic properties are modulated by the releasing or withdrawing power of the G group. The compounds were structurally characterized through single crystal Synchrotron X-ray diffraction experiments in the solid state, revealing that 1 (OMe) and 2 (H) adopt a dimeric assembly [Cu(μ-Cl)(GL)]2 through apical interaction of the chloride ions of two monomeric units, while 3 embraces a 1D polymeric chain structure [Cu(μ-Cl)(NO2L)]n with a similar bridging fashion, all supported by extended intramolecular or intrachain hydrogen bonds. The redox properties of the complexes were also studied by cyclic voltammetry with no marked effect of the substituent on the potential of the CuII/CuI redox system. UV/Vis spectroscopic studies in mimicked physiological conditions highlighted the intactness and stability of the coordinated NNO tridentate ligand in 1-3 and the lability of the coordinated chloride ion with the formation of the aquo-complexes [Cu(GL)(H2O)]+ in aqueous solution, as confirmed by conductance measurements with a 1 : 1 electrolyte molar conductivity. In vitro tests on cell viability were conducted on malignant cell lines typical for their poor prognosis and curability, revealing time-dependent and differential cytotoxicity given by the substituent G. All compounds were capable of formation of intracellular reactive oxygen species and DNA intercalation, acting as nuclease and producing double-strand DNA breaks. This is especially effective for 3 (NO2), which revealed the highest anticancer activity against malignant triple-negative breast cancer MDA-MB-231 cells, with a two-to-four-fold cytotoxicity enhancement with respect to 1 (OMe) and 2 (H), and, most important, substantial differentiation of cytotoxicity with respect to healthy endothelial HUVEC cell line.

Heart myxoma develops oncogenic and metastatic phenotype

Heart myxomas have been frequently considered as benign lesions associated with Carney's complex. However, after surgical removal, myxomas re-emerge causing dysfunctional heart. To identify whether cardiac myxomas may develop a metastatic phenotype as occurs in malignant cancers, a profile of several proteins involved in malignancy such as oncogenes (c-MYC, K-RAS and H-RAS), cancer-associated metabolic transcriptional factors (HIF-1α, p53 and PPAR-γ) and epithelial-mesenchymal transition proteins (fibronectin, vimentin, β-catenin, SNAIL and MMP-9) were evaluated in seven samples from a cohort of patients with atrial and ventricular myxomas. The analysis was also performed in: (1) cardiac tissue surrounding the area where myxoma was removed; (2) non-cancer heart tissue (NCHT); and (3) malignant triple negative breast cancer biopsies for comparative purposes. Statistical analysis applying univariate (Kruskal-Wallis and Dunn's tests) and multivariate analyses (PCA, principal component analysis) revealed that heart myxomas (7-15 times) and myxoma surrounding tissue (22-99 times) vs. NCHT showed high content of c-MYC, p53, vimentin, and HIF-1α, indicating that both myxoma and its surrounding area express oncogenes and malignancy-related proteins as occurs in triple negative breast cancer. Based on ROC (receiver operating characteristics) statistical analysis, c-MYC, HIF-1α, p53, and vimentin may be considered potential biomarkers for malignancy detection in myxoma.