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Oestrogen receptor-α (ERα) is a ligand-dependent transcription factor that primarily mediates oestrogen (E2)-dependent gene transcription required for mammary gland development. Coregulators critically regulate ERα transcription functions by directly interacting with it. In the present study, we report that ELF3, an epithelial-specific ETS transcription factor, acts as a transcriptional repressor of ERα. Co-immunoprecipitation (Co-IP) analysis demonstrated that ELF3 strongly binds to ERα in the absence of E2, but ELF3 dissociation occurs upon E2 treatment in a dose- and time-dependent manner suggesting that E2 negatively influences such interaction. Domain mapping studies further revealed that the ETS (E-twenty six) domain of ELF3 interacts with the DNA binding domain of ERα. Accordingly, ELF3 inhibited ERα's DNA binding activity by preventing receptor dimerization, partly explaining the mechanism by which ELF3 represses ERα transcriptional activity. Ectopic expression of ELF3 decreases ERα transcriptional activity as demonstrated by oestrogen response elements (ERE)-luciferase reporter assay or by endogenous ERα target genes. Conversely ELF3 knockdown increases ERα transcriptional activity. Consistent with these results, ELF3 ectopic expression decreases E2-dependent MCF7 cell proliferation whereas ELF3 knockdown increases it. We also found that E2 induces ELF3 expression in MCF7 cells suggesting a negative feedback regulation of ERα signalling in breast cancer cells. A small peptide sequence of ELF3 derived through functional interaction between ERα and ELF3 could inhibit DNA binding activity of ERα and breast cancer cell growth. These findings demonstrate that ELF3 is a novel transcriptional repressor of ERα in breast cancer cells. Peptide interaction studies further represent a novel therapeutic option in breast cancer therapy.

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In this study, we investigated a new series of naphthalimide based Schiff base compounds as potential DNA binding, antioxidant and antimicrobial agents. The structural characterization of synthesized compounds was carried out with the aid of elemental analysis and spectroscopic techniques (UV-vis., IR, (1)H and (13)C NMR). The DNA binding properties of target compounds against Ct-DNA (calf thymus) have been investigated in detail by numerous biophysical techniques (UV-vis, fluorescence, ethidium bromide displacement assay, Time resolved fluorescence, viscosity, cyclic voltammetry and circular dichorism) and the evidences have suggested that the test compounds could interact with DNA via intercalative binding. The extent of DNA binding (Kb) of these compounds follow the order of 3b (3.33 × 10(4) M(-1)) > 3a (2.25 × 10(4) M(-1)) > 3c (2 × 10(4) M(-1)), suggesting that compound 3b binds more strongly to Ct- DNA than the compounds 3a and 3c. Molecular docking results further support intercalative binding of test compounds with DNA. The binding energies of docked compounds (3a-3c) were found to be -8.20 to -8.69 kcal/ mol, suggesting greater binding affinity to Ct-DNA. The synthesized compounds displayed potential antimicrobial activities against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae and Salmonella typhimurium. Compound 3c has emerged as most active against all the four tested bacterial strains with MIC value in the range of 0.031-0.062 mg/mL. In the mutagenicity studies, all the test compounds were found to be non-mutagenic both in the presence and absence of metabolic activation. Furthermore, the antioxidant activity experiments show that these compounds exhibited potential scavenging activities against DPPH and H2O2 radicals.

Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers.