Novel insights into breast cancer genetic variance through RNA sequencing

Using RNA sequencing of triple-negative breast cancer (TNBC), non-TBNC and HER2-positive breast cancer sub-types, here we report novel expressed variants, allelic prevalence and abundance, and coexpression with other variation, and splicing signatures. To reveal the most prevalent variant alleles, we overlaid our findings with cancer- and population-based datasets and validated a subset of novel variants of cancer-related genes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8. As a proof-of-principle, we demonstrated that a rare substitution in the splicing coordinator ESRP2(R353Q) impairs its ability to bind to its substrate FGFR2 pre-mRNA. In addition, we describe novel SNPs and INDELs in cancer relevant genes with no prior reported association of point mutations with cancer, such as MTAP and MAGED1. For the first time, this study illustrates the power of RNA-sequencing in revealing the variation landscape of breast transcriptome and exemplifies analytical strategies to search regulatory interactions among cancer relevant molecules

Arpc1b, a centrosomal protein, is both an activator and substrate of Aurora A

In addition to its function as an Arp2/3 complex subunit, Arp1cb interacts with and stimulates Aurora A at centrosomes, functioning in cell cycle progression

Metastasis-associated protein 1 short form stimulates Wnt1 pathway in mammary epithelial and cancer cells

Although Wnt1 downstream signaling components as well as cytoplasmic level of metastatic tumor antigen 1 short-form (MTA1s) have been shown to be elevated in human breast cancer, it remains unknown whether a regulatory cross-talk exists between these two pathways. Here we provide evidence of a remarkable correlation between the levels of MTA1s and stimulation of the Wnt1 signaling components, leading to increased stabilization of β-catenin, and stimulation of Wnt1 target genes in the murine mammary epithelial and human breast cancer cells. We found that MTA1s influences Wnt1 pathway via ERK signaling as selective silencing of the endogenous MTA1s or ERK or its target GSK-3β resulted in a substantial decrease in β-catenin expression, leading to inhibition of Wnt1-target genes. Furthermore, downregulation of β-catenin in cells with elevated MTA1s level was accompanied by a corresponding decrease in the expression of Wnt1 target genes, establishing a mechanistic role for the ERK/GSK-3β/ β-catenin pathway in the stimulation of the Wnt1 target genes by MTA1s in mammary epithelial cells. In addition, mammary glands from the virgin MTA1s transgenic mice mimicked the phenotypic changes found in the Wnt1 transgenic mice and exhibited an overall hyperactivation of the Wnt1 signaling pathway, leading to increased stabilization and nuclear accumulation of β-catenin. Mammary glands from the virgin MTA1s-TG mice revealed ductal hyperplasia and ductal carcinoma in situ, and low incidence of palpable tumors. These findings reveal a previously unrecognized role for MTA1s as an important modifier of the Wnt1 signaling in mammary epithelial and cancer cells

Bioinformatics exploration of PAK1 (P21-activated kinase-1) revealed potential network gene elements in breast invasive carcinoma

<p>P21-activated kinase-1 (PAK1) is an enzyme associated with multiple metabolic networks and different types of cancers. Hence, there is a need to study the global network map of PAK1 to understand its role and regulatory mechanisms by means of its significant molecular interactive partners. This will help to explore its global biological functions in breast cancer. In view of this, we obtained the gene expression data-sets of PAK1 from The Cancer Genome Atlas-cBioportal and GeneCards databases and found that 91 PAK1-related genes are associated with breast cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway investigations of 91 genes via Database for Annotation Visualization and Integrated Discovery bioinformatics resource revealed that, PAK1 being a major kinase is associated with several metabolic pathways and involved in phosphorylation, signal transduction, apoptosis, biosynthesis and majorly cancer-related cell signalling pathways. The PAK1 interaction network derived from STRING and Cytoscape revealed that the genes Signal-Transducer-and-Activator-of-Transcription-3 (STAT3), Cyclin-D1 (CCND1), Mitogen-activated protein kinase-1 (MAPK1), Ras-Homolog-Family-Member-A (RHOA) and Catenin-beta-1 have high degrees of interaction where CCND1, MAPK1 and RHOA have direct interaction with PAK1. Finally, the global expression map of PAK1 and its related genes was derived as topological frame that helped to explore and investigate PAK1 interactions. Further, the molecular modelling studies of PAK1 with its major interacting partners RHOA and STAT3 helped to explore the key interactive residues of PAK1 structure. This information can be used to develop novel therapeutic and control strategies against breast cancer.</p

PAK thread from amoeba to mammals

The p21-activated kinases (PAKs) are signaling nodes that play a crucial role in cellular processes including cell motility, differentiation, survival, gene transcription and hormone signaling. PAKs are highly conserved family of serine threonine kinases that act as effector for small GTPases Rac and Cdc42. Most of our knowledge about PAK functions has been derived from genetic approaches in lower organisms and many of these functions are similar to that seen in mammalian cells. In this review, we have summarized the extensive information generated in lower eukaryotes and very briefly discussed the current status of PAKs in humans

Transposon-Like Organization of the Plasmid-Borne Organophosphate Degradation (opd) Gene Cluster Found in Flavobacterium sp.

Several bacterial strains that can use organophosphate pesticides as a source of carbon have been isolated from soil samples collected from diverse geographical regions. All these organisms synthesize an enzyme called parathion hydrolase, and in each case the enzyme is encoded by a gene (opd) located on a large indigenous plasmid. These plasmids show considerable genetic diversity, but the region containing the opd gene is highly conserved. Two opd plasmids, pPDL2 from Flavobacterium sp. and pCMS1 from Pseudomonas diminuta, are well characterized, and in each of them a region of about 5.1 kb containing the opd gene shows an identical restriction pattern. We now report the complete sequence of the conserved region of plasmid pPDL2. The opd gene is flanked upstream by an insertion sequence, ISFlsp1, that is a member of the IS21 family, and downstream by a Tn3-like element encoding a transposase and a resolvase. Adjacent to opd but transcribed in the opposite direction is an open reading frame (orf243) with the potential to encode an aromatic hydrolase somewhat similar to Pseudomonas putida TodF. We have shown that orf243 encodes a polypeptide of 27 kDa, which plays a role in the degradation of p-nitrophenol and is likely to act in concert with opd in the degradation of parathion. The linkage of opd and orf243, the organization of the genes flanking opd, and the wide geographical distribution of these genes suggest that this DNA sequence may constitute a complex catabolic transposon