Objectives:. To investigate the association between PTEN loss and IGFBP2 expression in a series of triple-negative breast cancers and to relate this ex

Hyperglycaemia is a common metabolic alteration associated with breast cancer risk and progression. We have previously reported that BRCA1 restrains metabolic activity and proliferative response to IGF-I anabolic actions in breast cancer cells cultured in high glucose. Here, we evaluated the impact of normal physiological glucose on these tumour suppressive roles of BRCA1. Human breast cancer cells cultured in normal physiological and high glucose were treated with IGF-I (0–500 ng/mL). Cellular responses were evaluated using immunoblotting, co-immunoprecipitation, and cell viability assay. As we previously reported, IGF-I induced ACCA dephosphorylation by reducing the association between BRCA1 and phosphorylated ACCA in high glucose, and upregulated FASN abundance downstream of ACCA. However, these effects were not observed in normal glucose. Normal physiological glucose conditions completely blocked IGF-I-induced ACCA dephosphorylation and FASN upregulation. Co-immunoprecipitation studies showed that normal physiological glucose blocked ACCA dephosphorylation by increasing the association between BRCA1 and phosphorylated ACCA. Compared to high glucose, the proliferative response of breast cancer cells to IGF-I was reduced in normal glucose, whereas no difference was observed in normal mammary epithelial cells. Considering these results collectively, we conclude that normal physiological glucose promotes the novel function of BRCA1 as a metabolic restraint of IGF-I actions. These data suggest that maintaining normal glucose levels may improve BRCA1 function in breast cancer and slow down cancer progression.

Elucidating the novel BRCA1 function as a non-genomic metabolic restraint in ER-positive breast cancer cell lines Elucidating the novel BRCA1 function as a non-genomic metabolic restraint in ER-positive breast cancer cell lines

A new polypyridyl ligand 4‐(4‐nitrophenoxy)‐N,N‐bis (pyridin‐2‐ylmethyl)aniline (L1) and its three ruthenium (II/III) complexes, [Ru (Cl)₃L1] (C1), [Ru(L1)₂]Cl (C2), and [RuCl (dpa)L1] (C3) where dpa = 2,2‐dipyridylamine, have been successfully synthesized and characterized using Fourier‐transform infrared spectroscopy (FTIR), elemental analysis, proton nuclear magnetic resonance (¹H NMR), high‐resolution electrospray ionization mass spectrometry (HR‐ESI‐MS), thermal analysis (thermogravimetric analysis [TGA] and differential scanning calorimetry [DSC]), UV/Vis absorption, and magnetic susceptibility. The structures of the ligand and the complexes were optimized, and the structural characteristics were determined by density functional theory (DFT) using the B3LYP‐GD3/6‐311G++(d,p) method. Optimized FTIR vibrational frequencies and ¹H NMR chemical shifts agreed well with the corresponding experimental FTIR and ¹H NMR data. In vitro cytotoxicity of the ligand and the complexes were evaluated against the MCF‐7 breast cancer cell line. Ligand L1 was the most potent with an IC₅₀ of 38.45 μM, followed by C2 with an IC₅₀ of 45.23 μM. However, the ligand and the complexes showed low antiproliferative activity compared to cisplatin, which had an IC₅₀ of 9.67 μM. To predict the reactivity trend of L1 and the complexes, frontier molecular orbital (FMO) analysis was performed. The FMO energy gap (Eg = E_LUMO − E_HOMO) for C2 was found to be 1.675 eV, which was the lowest among all the complexes or L1. In addition, molecular docking studies were carried out so as to predict the binding capacity of L1 and the complexes to estrogen receptor alpha (ER‐α). The results showed that C2 has the most negative binding energy score (−9.63 kcal/mol), which indicates more stable adducts with the key amino acid residues at the active sites of ER‐α. Furthermore, C2 displayed the lowest inhibition constant (K_i) of 0.09 μM compared to all the complexes or L1. These results are very promising and show that the novel complex C2 may help in the development of anticancer drugs.

A series of ester and ether bridged compounds bearing the nitro and amino moieties were synthesized and characterized inorder to assess their ability to potentially serve as antibacterial agents against drug resistant bacteria. All the compounds were obtained at considerable yields while characterization techniques confirmed their succesful synthesis. Furthermore, their antimicrobial assesments showed that all the compounds exhibited antibacterial activity against the Gram-negative bacterial strains, both Klebsiella pneumoniae and its drug resistant counterpart. On the contrary they were poorly active against S. aureus and MRSA. According to the MIC data all the compounds showed activity of 0.22 to 0.24 mM towards MDR-K. pneumonieae. As for K. pneumoniae, the nitro derivatives L1 and L4 showed significantly higher MIC of 0.23 and 0.26 mM respectivelly while the amino derivatives L2 and L3 were more active, with MIC values of 0.16 mM. Finally, the time kill kinetics study showed that L2 and L3 were bacteriostatic while L1 and L4 were bactericidal towards K. pneumoniae. However, all the compounds were bactericidal towards MDR- K. pneumoniae.