Identifying breast cancer subtypes associated modules and biomarkers by integrated bioinformatics analysis

Breast cancer is the most common form of cancer afflicting women worldwide. Patients with breast cancer of different molecular classifications need varied treatments. Since it is known that the development of breast cancer involves multiple genes and functions, identification of functional gene modules (clusters of the functionally related genes) is indispensable as opposed to isolated genes, in order to investigate their relationship derived from the gene co-expression analysis. In total, 6315 differentially expressed genes (DEGs) were recognized and subjected to the co-expression analysis. Seven modules were screened out. The blue and turquoise modules have been selected from the module trait association analysis since the genes in these two modules are significantly correlated with the breast cancer subtypes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment show that the blue module genes engaged in cell cycle, DNA replication, p53 signaling pathway, and pathway in cancer. According to the connectivity analysis and survival analysis, 8 out of 96 hub genes were filtered and have shown the highest expression in basal-like breast cancer. Furthermore, the hub genes were validated by the external datasets and quantitative real-time PCR (qRT-PCR). In summary, hub genes of Cyclin E1 (CCNE1), Centromere Protein N (CENPN), Checkpoint kinase 1 (CHEK1), Polo-like kinase 1 (PLK1), DNA replication and sister chromatid cohesion 1 (DSCC1), Family with sequence similarity 64, member A (FAM64A), Ubiquitin Conjugating Enzyme E2 C (UBE2C) and Ubiquitin Conjugating Enzyme E2 T (UBE2T) may serve as the prognostic markers for different subtypes of breast cancer.     

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

Regulation of mRNA stability and translation plays a critical role in determining protein abundance within cells. Processing bodies (P‐bodies) are critical regulators of these processes. Here, we report that the Pim1 and 3 protein kinases bind to the P‐body protein enhancer of mRNA decapping 3 (EDC3) and phosphorylate EDC3 on serine (S)161, thereby modifying P‐body assembly. EDC3 phosphorylation is highly elevated in many tumor types, is reduced upon treatment of cells with kinase inhibitors, and blocks the localization of EDC3 to P‐bodies. Prostate cancer cells harboring an EDC3 S161A mutation show markedly decreased growth, migration, and invasion in tissue culture and in xenograft models. Consistent with these phenotypic changes, the expression of integrin β1 and α6 mRNA and protein is reduced in these mutated cells. These results demonstrate that EDC3 phosphorylation regulates multiple cancer‐relevant functions and suggest that modulation of P‐body activity may represent a new paradigm for cancer treatment.     

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl₂] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl₂), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl₂)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl₂ compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl₂ was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.