Lympho-vascular invasion in BRCA related breast cancer compared to sporadic controls

<p>Abstract</p> <p>Background</p> <p>Germline mutations in the BRCA1 gene predispose to the development of breast cancer, exhibiting a specific histological phenotype. Identification of possible hallmarks of these tumors is important for selecting patients for genetic screening and provides inside in carcinogenetic pathways.</p> <p>Since BRCA1-associated breast cancers have pushing borders that prevent them from easily reaching vessels and are often of the medullary (like) type that is known to have a low rate of lympho-vascular invasion (LVI), we hypothesized that absence of LVI could characterize BRCA1 related breast cancer.</p> <p>Methods</p> <p>A population of 68 BRCA1 related invasive breast cancers was evaluated for LVI by an experienced breast pathologist blinded to mutation status, and compared to a control group matched for age, grade and tumor type.</p> <p>Results</p> <p>LVI was present in 25.0% of BRCA1 related cases, compared to 20.6% of controls (P = 0.54, OR = 1.29, CI 0.58-2.78).</p> <p>Conclusion</p> <p>LVI is frequent in BRCA1 germline mutation related breast cancers, but seems to occur as often in sporadic controls matched for age, grade and tumor type. Apparently, these hereditary cancers find their way to the blood and lymph vessels despite their well demarcation and often medullary differentiation.</p

An improved method for scoring protein-protein interactions using semantic similarity within the gene ontology

<p>Abstract</p> <p>Background</p> <p>Semantic similarity measures are useful to assess the physiological relevance of protein-protein interactions (PPIs). They quantify similarity between proteins based on their function using annotation systems like the Gene Ontology (GO). Proteins that interact in the cell are likely to be in similar locations or involved in similar biological processes compared to proteins that do not interact. Thus the more semantically similar the gene function annotations are among the interacting proteins, more likely the interaction is physiologically relevant. However, most semantic similarity measures used for PPI confidence assessment do not consider the unequal depth of term hierarchies in different classes of cellular location, molecular function, and biological process ontologies of GO and thus may over-or under-estimate similarity.</p> <p>Results</p> <p>We describe an improved algorithm, Topological Clustering Semantic Similarity (TCSS), to compute semantic similarity between GO terms annotated to proteins in interaction datasets. Our algorithm, considers unequal depth of biological knowledge representation in different branches of the GO graph. The central idea is to divide the GO graph into sub-graphs and score PPIs higher if participating proteins belong to the same sub-graph as compared to if they belong to different sub-graphs.</p> <p>Conclusions</p> <p>The TCSS algorithm performs better than other semantic similarity measurement techniques that we evaluated in terms of their performance on distinguishing true from false protein interactions, and correlation with gene expression and protein families. We show an average improvement of 4.6 times the <it>F</it>₁score over Resnik, the next best method, on our <it>Saccharomyces cerevisiae </it>PPI dataset and 2 times on our <it>Homo sapiens </it>PPI dataset using cellular component, biological process and molecular function GO annotations.</p

Immunophenotypic predictive profiling of BRCA1-associated breast cancer

The immunophenotypic predictive profile of BRCA1-associated cancers including major predictive markers, i.e., PARP-1, EGFR, c-kit, HER-2, and steroid hormones (ER/PR) that may have therapeutic relevance has not yet been reported in a comprehensive study. Using immunohistochemistry, we examined the expression of these proteins in a large cohort of BRCA1-associated breast cancers. PARP-1 immunoreactivity was found in 81.9%, EGFR in 43.6%, ER/PR in 17.9%, c-kit in 14.7%, and overexpression of HER-2 in 3.6% of cancers. For all markers studied, 8.2% of tumors were negative. Expression of only one predictive marker was found in 29.7% of cancers, and most frequently, it was PARP-1 (20.8%). In 62.1% of tumors, more than one predictive marker was expressed: PARP-1 and EGFR in 30.4%, PARP-1, and hormone receptors in 13.3% and PARP-1 with c-kit in 7.5% of all tumors. Coexpression of two or more other predictive markers was rare. There were significant differences in the median age at diagnosis of BRCA1-associated cancer between patients with ER+ vs. ER− and grades 1–2 vs. grade 3 tumors. These results demonstrate that BRCA1-associated cancers differ with respect to expression of proteins that are regarded as targets for specific therapies and that 92% of patients with BRCA1-associated cancers may benefit from one or several options for specific therapy (in addition to DNA damaging agents, e.g., cisplatin). About 8% of cancers which do not express therapeutic target proteins may not respond to such therapies. Knowledge of the immunophenotypic predictive profile may help with the recruitment of patients for trials of targeted therapies

Regulated Nuclear Trafficking of rpL10A Mediated by NIK1 Represents a Defense Strategy of Plant Cells against Virus

The NSP-interacting kinase (NIK) receptor-mediated defense pathway has been identified recently as a virulence target of the geminivirus nuclear shuttle protein (NSP). However, the NIK1–NSP interaction does not fit into the elicitor–receptor model of resistance, and hence the molecular mechanism that links this antiviral response to receptor activation remains obscure. Here, we identified a ribosomal protein, rpL10A, as a specific partner and substrate of NIK1 that functions as an immediate downstream effector of NIK1-mediated response. Phosphorylation of cytosolic rpL10A by NIK1 redirects the protein to the nucleus where it may act to modulate viral infection. While ectopic expression of normal NIK1 or a hyperactive NIK1 mutant promotes the accumulation of phosphorylated rpL10A within the nuclei, an inactive NIK1 mutant fails to redirect the protein to the nuclei of co-transfected cells. Likewise, a mutant rpL10A defective for NIK1 phosphorylation is not redirected to the nucleus. Furthermore, loss of rpL10A function enhances susceptibility to geminivirus infection, resembling the phenotype of nik1 null alleles. We also provide evidence that geminivirus infection directly interferes with NIK1-mediated nuclear relocalization of rpL10A as a counterdefensive measure. However, the NIK1-mediated defense signaling neither activates RNA silencing nor promotes a hypersensitive response but inhibits plant growth and development. Although the virulence function of the particular geminivirus NSP studied here overcomes this layer of defense in Arabidopsis, the NIK1-mediated signaling response may be involved in restricting the host range of other viruses

Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer

Breast cancers related to BRCA mutations are associated with particular biological features. Here we report the clinical and pathological characteristics of breast cancer in Chinese women with and without BRCA mutations and of carriers of BRCA1 mutations compared to BRCA2 mutations. Two hundred and 26 high-risk Hong Kong Chinese women were tested for BRCA mutations, medical information was obtained from medical records, and risk and demographic information was obtained from personal interviews. In this cohort, 28 (12.4%) women were BRCA mutation carriers and among these carriers, 39.3% were BRCA1 and 60.7% were BRCA2 mutations. Mutation carriers were more likely to have a familial history of breast and ovarian cancer, high-grade cancers, and triple negative (TN) cancers. Prevalence of TN was 48.3% in BRCA carriers and 25.6% in non-carriers and was 67.7% in BRCA1 and 35.3% in BRCA2 carriers. Estrogen receptor (ER) negative cancer was significantly associated with BRCA1 mutations, especially in those under 40 years of age. BRCA-related breast cancer in this Chinese population is associated with family history and adverse pathological/prognostic features, with BRCA2 mutations being more prevalent but BRCA1 carriers having more aggressive and TN cancers. Compared to Caucasian populations, prevalence of BRCA2 mutations and TN cancer in BRCA2 mutation carriers in Chinese population are elevated

Release of the export adapter, Nmd3p, from the 60S ribosomal subunit requires Rpl10p and the cytoplasmic GTPase Lsg1p

In eukaryotes, nuclear export of the large (60S) ribosomal subunit requires the adapter protein Nmd3p to provide the nuclear export signal. Here, we show that in yeast release of Nmd3p from 60S subunits in the cytoplasm requires the ribosomal protein Rpl10p and the G-protein, Lsg1p. Mutations in LSG1 or RPL10 blocked Nmd3-GFP shuttling into the nucleus and export of pre-60S subunits from the nucleus. Overexpression of NMD3 alleviated the export defect, indicating that the block in 60S export in lsg1 and rpl10 mutants results indirectly from failing to recycle Nmd3p. The defect in Nmd3p recycling and the block in 60S export in both lsg1 and rpl10 mutants was also suppressed by mutant Nmd3 proteins that showed reduced binding to 60S subunits in vitro. We propose that the correct loading of Rpl10p into 60S subunits is required for the release of Nmd3p from subunits by Lsg1p. These results suggest a coupling between recycling the 60S export adapter and activation of 60S subunits for translation

Reduction of Qm Protein Expression Correlates with Tumor Grade in Prostatic Adenocarcinoma

The QM protein is a transcription cofactor inhibiting the activity of AP-1 transcription factors and is also a ribosomal protein participating in protein synthesis. While protein synthesis is known to be increased in many cancers, inhibition of AP-1 activity presumably suppresses development and growth of sex-hormone-regulated tumor cells. The present study is the first report on immunohistochemical data of QM in human prostatic tissues. Paraffin sections of human prostate cancer samples were immunohistochemically stained for QM. The staining scores were analyzed with the clinicopathologic data of the patients. QM protein expression was found in all normal prostate glands adjacent to prostate cancer and in various intraepithelial neoplasia ( PIN). In prostate cancer, the staining intensity and stained areas were decreased, compared to the normal glands and PIN lesions; in high-grade tumors only some patches of tumor cells showed positivity. Intense (3+) staining was mostly observed in the Gleason grade three areas (48%) compared to grade 4 and 5 areas (22%), although both low and high-grade tumors showed similar percentages of weakly stained areas. Moreover, staining in prostatic adenocarcinoma was often topographically patchy and varied from negative or weak (1+) to intense (3+). There was an inverse correlation from normal to low-grade tumors and then to high-grade tumors. However, in high-grade tumors, the positive areas were mostly confined to peripheral aspects of tumors and were particularly strong in foci of perineural invasion. This preliminary study suggests that decreased QM expression may be associated with early development of prostate cancer, but later a high level of QM may facilitate progression of the tumors to a more aggressive phenotype.WoSScopu