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Although the incidence of invasive breast cancer (BC) among women in Asian is generally lower than that in Western countries, the incidence of BC has been on the rise in the past three decades in Asian countries. This hospital-based case-control study aimed to explore the relationship between dietary and metabolic factors and BC risk in pre- and post-menopausal women. We enrolled 285 patients with newly diagnosed BC at the National Taiwan University Hospital and 297 controls from the local community and hospital staff. Before receiving anticancer therapy, all patients with BC and control participants completed a 57-question semi-quantitative Food Frequency Questionnaire. For pre-menopausal women, plant-based factor scores rich in seeds and nuts, soy, fruits, and seaweeds correlated significantly with reduced BC risks, whereas menarche occurring at <12 years of age, reduced physical activity, and high-density lipoprotein <40 mg/dL were associated with increased BC risks. For post-menopausal women, plant-based dietary factor scores were also associated with reduced risks, whereas increased body mass index and energy intake levels correlated with increased BC risks. Diets rich in plant-based dietary patterns are protective against BC risk, regardless of menopausal status. Habitual physical activity is protective against BC risk among pre-menopausal Taiwanese women. Maintaining optimal weight and caloric intake is beneficial for reducing post-menopausal BC risk. [ABSTRACT FROM AUTHOR]

A series of imidazolium salt derivatives have demonstrated potent antitumor activity in prior research. A comprehensive in silicon method was carried out to identify the putative protein target and detailed structure-activity relationship of the compounds. The Topomer CoMFA and CoMSIA techniques were implemented during the investigation to obtain the relationship between the properties of the substituent group and the contour map of around 77 compounds; the Topomer CoMFA and CoMSIA models were reliable with the statistical data. The protein-protein interaction network was constructed by combining the Pharmmapper platform and STRING database. After generating the sub-network, the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA with protein data bank ID: 3ZIM) was selected as the putative target of imidazolium salt derivatives. A docking study was carried out to correlate interactions of amino acids in protein active pockets surrounded by the ligand with contour maps generated by the structure-activity relationship method. Then the molecular dynamics simulations demonstrated that the imidazolium salt derivatives have potent binding capacity and stability to receptor 3ZIM, and the two ligand-receptor complex was stable in the last 2 ns. Finally, the ligand-based structure-activity relationship and receptor-based docking were combined together to identify the structural requirement of the imidazolium salt derivatives, which will be used to design and synthesize the novel PIK3CA inhibitors. [ABSTRACT FROM AUTHOR]

TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of the tumor microenvironment which induces hypoxia-inducible factor-1α (HIF-1α) for transcriptional regulation. HIF-1α is prone to be rapidly destabilized by the ubiquitination–proteasomal degradation system. In this study, we found that TARBP2 expression is significantly correlated with induced hypoxia signatures in human breast cancer tissues. At a cellular level, HIF-1α protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1α protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1α (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1α were also induced by TARBP2. In support of our clinical findings that TARBP2 is correlated with tumor hypoxia, our IHC staining showed the positive correlation between HIF-1α and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination–proteasomal degradation of HIF-1α protein in breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: SnoRNAs are essential for fundamental cellular processes. However, emerging evidence shows that snoRNAs play regulatory roles during cancer progression. The snoRNA U50A (U50A) is a newly-identified putative tumor suppressor, but its clinical and mechanistic impacts in breast cancer remain elusive. In this study, we quantified the copy number of U50A in breast cancer patient tissues and found that a higher level of U50A expression is correlated with better overall survival in breast cancer patients. By utilizing transcriptomic analysis, we demonstrated that U50A prolongs mitosis and reduces colony-forming ability through downregulating mitosis-related genes. Consistent with these in vitro results, breast cancer tissues expressing higher U50A significantly exhibited accumulated mitotic tumor cells and were associated with reduced tumor size. Altogether, this is the first study showing the clinical, cellular, and regulatory impacts of snoRNA U50A in human breast cancer. Small nucleolar RNAs (snoRNAs) are small noncoding RNAs generally recognized as housekeeping genes. Genomic analysis has shown that snoRNA U50A (U50A) is a candidate tumor suppressor gene deleted in less than 10% of breast cancer patients. To date, the pathological roles of U50A in cancer, including its clinical significance and its regulatory impact at the molecular level, are not well-defined. Here, we quantified the copy number of U50A in human breast cancer tissues. Our results showed that the U50A expression level is correlated with better prognosis in breast cancer patients. Utilizing RNA-sequencing for transcriptomic analysis, we revealed that U50A downregulates mitosis-related genes leading to arrested cancer cell mitosis and suppressed colony-forming ability. Moreover, in support of the impacts of U50A in prolonging mitosis and inhibiting clonogenic activity, breast cancer tissues with higher U50A expression exhibit accumulated mitotic tumor cells. In conclusion, based on the evidence from U50A-downregulated mitosis-related genes, prolonged mitosis, repressed colony-forming ability, and clinical analyses, we demonstrated molecular insights into the pathological impact of snoRNA U50A in human breast cancer. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3 kinase delta (PI3Kδ) is a lipid kinase that has been implicated in a variety of immune mediated disorders. The research on isoform selectivity was crucial for reducing side effects. In the current study, an optimized hierarchical multistage virtual screening method was utilized for screening the PI3Kδ selective inhibitors. The method sequentially applied a support vector machine (SVM), a protein ligand interaction fingerprint (PLIF) pharmacophore, and a molecular docking approach. The evaluation of the validation set showed a high hit rate and a high enrichment factor of 75.1% and 301.66, respectively. This multistage virtual screening method was then utilized to screen the NCI database. From the final hit list, Compound 10 has great potential as the PI3Kδ inhibitor with micromolar inhibition in the PI3Kδ kinase activity assay. This compound also shows selectivity against PI3Kδ kinase. The method combining SVM, pharmacophore, and docking was capable of screening out the compounds with potential PI3Kδ selective inhibitors. Moreover, structural modification of Compound 10 will contribute to investigating the novel scaffold and designing novel PI3Kδ inhibitors. [ABSTRACT FROM AUTHOR]

Tamoxifen is the most widely used hormone therapy in estrogen receptor-positive (ER+) breast cancer, which accounts for approximately 70% of all breast cancers. Although patients who receive tamoxifen therapy benefit with respect to an improved overall prognosis, resistance and cancer recurrence still occur and remain important clinical challenges. A recent study identified TAR (HIV-1) RNA binding protein 2 (TARBP2) as an oncogene that promotes breast cancer metastasis. In this study, we showed that TARBP2 is overexpressed in hormone therapy-resistant cells and breast cancer tissues, where it enhances tamoxifen resistance. Tamoxifen-induced TARBP2 expression results in the desensitization of ER+ breast cancer cells. Mechanistically, tamoxifen post-transcriptionally stabilizes TARBP2 protein through the downregulation of Merlin, a TARBP2-interacting protein known to enhance its proteasomal degradation. Tamoxifen-induced TARBP2 further stabilizes SOX2 protein to enhance desensitization of breast cancer cells to tamoxifen, while similar to TARBP2, its induction in cancer cells was also observed in metastatic tumor cells. Our results indicate that the TARBP2-SOX2 pathway is upregulated by tamoxifen-mediated Merlin downregulation, which subsequently induces tamoxifen resistance in ER+ breast cancer. [ABSTRACT FROM AUTHOR]

Marine animals and plants provide abundant secondary metabolites with antitumor activity. Itampolin A is a brominated natural tyrosine secondary metabolite that is isolated from the sponge Iotrochota purpurea. Recently, we have achieved the first total synthesis of this brominated tyrosine secondary metabolite, which was found to be a potent p38α inhibitor exhibiting anticancer effects. A fragment-based drug design (FBDD) was carried out to optimize itampolin A. Forty-five brominated tyrosine derivatives were synthesized with interesting biological activities. Then, a QSAR study was carried out to explore the structural determinants responsible for the activity of brominated tyrosine skeleton p38α inhibitors. The lead compound was optimized by a FBDD method, then three series of brominated tyrosine derivatives were synthesized and evaluated for their inhibitory activities against p38α and tumor cells. Compound 6o (IC50 = 0.66 μM) exhibited significant antitumor activity against non-small cell lung A549 cells (A549). This also demonstrated the feasibility of the FBDD method of structural optimization. [ABSTRACT FROM AUTHOR]

TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of the tumor microenvironment which induces hypoxia-inducible factor-1α (HIF-1α) for transcriptional regulation. HIF-1α is prone to be rapidly destabilized by the ubiquitination-proteasomal degradation system. In this study, we found that TARBP2 expression is significantly correlated with induced hypoxia signatures in human breast cancer tissues. At a cellular level, HIF-1α protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1α protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1α (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1α were also induced by TARBP2. In support of our clinical findings that TARBP2 is correlated with tumor hypoxia, our IHC staining showed the positive correlation between HIF-1α and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination-proteasomal degradation of HIF-1α protein in breast cancer.

A combined in silico method was developed to predict potential protein targets that are involved in cardiotoxicity induced by aconitine alkaloids and to study the quantitative structure⁻toxicity relationship (QSTR) of these compounds. For the prediction research, a Protein-Protein Interaction (PPI) network was built from the extraction of useful information about protein interactions connected with aconitine cardiotoxicity, based on nearly a decade of literature and the STRING database. The software Cytoscape and the PharmMapper server were utilized to screen for essential proteins in the constructed network. The Calcium-Calmodulin-Dependent Protein Kinase II alpha (CAMK2A) and gamma (CAMK2G) were identified as potential targets. To obtain a deeper insight on the relationship between the toxicity and the structure of aconitine alkaloids, the present study utilized QSAR models built in Sybyl software that possess internal robustness and external high predictions. The molecular dynamics simulation carried out here have demonstrated that aconitine alkaloids possess binding stability for the receptor CAMK2G. In conclusion, this comprehensive method will serve as a tool for following a structural modification of the aconitine alkaloids and lead to a better insight into the cardiotoxicity induced by the compounds that have similar structures to its derivatives.