hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling

The increased cap-independent translation of anti-apoptotic proteins is involved in the development of drug resistance in lung cancer but signalling events regulating this are poorly understood. Fibroblast growth factor 2 (FGF-2) signalling-induced S6 kinase 2 (S6K2) activation is necessary, but the downstream mediator(s) coupling this kinase to the translational response is unknown. Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. In the cytoplasm, phosphoS4/6-hnRNPA1 dissociates from these mRNAs de-repressing their IRES-mediated translation. This correlates with the phosphorylation-dependent association of hnRNPA1 with 14-3-3 leading to hnRNPA1 sumoylation on K183 and its re-import into the nucleus. A non-phosphorylatible, S4/6A mutant prevented these processes, hindering the pro-survival activity of FGF-2/S6K2 signalling. Interestingly, immunohistochemical staining of lung and breast cancer tissue samples demonstrated that increased S6K2 expression correlates with decreased cytoplasmic hnRNPA1 and increased BCL-XL expression. In short, phosphorylation on novel N-term sites of hnRNPA1 promotes translation of anti-apoptotic proteins and is indispensable for the pro-survival effects of FGF-2

Proliferative activity in human breast cancer: Ki-67 automated evaluation and the influence of different Ki-67 equivalent antibodies

<p>Abstract</p> <p>Background</p> <p>Ki67 labeling index (Ki67 LI), the percentage Ki67 immunoreactive cells, is a measure of tumor proliferation, with important clinical relevance in breast cancer, and it is extremely important to standardize its evaluation.</p> <p>Aim</p> <p>To test the efficacy of computer assisted image analysis (CAIA) applied to completely digitized slides and to assess its feasibility in routine practice and compare the results obtained using two different Ki67 monoclonal antibodies.</p> <p>Materials and methods</p> <p>315 consecutive breast cancer routinely immunostained for Ki-67 (223 with SP6 and 92 with MM1 antibodies previously examined by an experienced pathologist, have been re-evaluated using Aperio Scanscope Xs.</p> <p>Results</p> <p>Mean human Ki67 LI values were 36%± 14.% and 28% ± 18% respectively for SP6 and MM1 antibodies; mean CAM Ki67 LI values were 31%± 19% and 22% ± 18% respectively for SP6 and MM1. Human and CAIA evaluation are statistically highly correlated (Pearson: 0.859, p<0.0001), although human LI are systematically higher. An interobserver variation study on CAIA performed on 84 cases showed that the correlation between the two evaluations was linear to an excellent degree.</p> <p>Discussion</p> <p>Our study shows that a) CAIA can be easily adopted in routine practice, b) human and CAIA Ki67 LI are highly correlated, although human LI are systematically higher, c) Ki67 LI using different evaluation methods and different antibodies shows important differences in cut-off values.</p

Invasive lobular (ILC) versus invasive ductal (IDC) breast cancer (BC): Clinical-pathologic features and clinical outcomes in monoinstitutional series

Background: ILC is less common than IDC and is usually diagnosed at a later stage Purpose:The aim of our study was to investigate different clinico-biological behavior associated to ILC compared to IDC and to evaluate implications on survival outcomes Methods: We analyzed data from 3749 consecutive cases of IBC treated from 1995 to 2008 and classified as ILC, IDC and mixed/other. Relationships with clinical-pathological variables and the impact of ILC/IDC types on Event Free Survival (EFS), Overall Survival (OS) and Post-Progression Survival (PPS) were analyzed. Results: We have identified 445 ILC BC (12%), 3021 IDC (80.5%), 149 mixed (3.9%) and 134 other histotypes (3.6%). Median age was 61 (25-97) years. ILC presented a significantly (p3 ILC pts, in whom a trend of worse prognosis (55.6 vs 60.2%) was observed. Conclusions: ILC pts did not show in our series a better outcome than IDC pts, despite a quite favorable biological pattern

Role of Ki67 labeling index (LI) in subdividing homogeneous ER-positive grading groups of early breast cancer (EBC) in distinct biologic entities

Background: Ki67LI is a relevant marker EBC. The 2009 St Gallen Consensus considered Ki67LI as an important parameter for the addition of chemotherapy to endocrine therapy in hormonereceptor-positive EBC, suggesting three cutoffs: low 30%. Our study aimed to evaluate if these cutoffs can be used in different subgroups of EBC, or if to apply different cutoffs in distinct biological setting. Methods: Ki67LI 1 was identified by immunohistochemical staining in 3802 EBC pts treated from 1995 to 2008. Median age was 61. The relationship with clinic-pathological parameters and the prognostic significance of KI67LI was investigated in all EBCs and in subgroups of ER+ cases based on homogeneous grading (656 G1, 1535 G2, 1113 G3). Results: Median Ki67LI values were 22% in all cases and 10, 20 and 36% in ER+ G1, G2 and G3 respectively. High Ki67LI was significantly (p<0.001) associated with younger age, ductal type, greater size, positive N, poor G, absent or low ER /PR, positive HER-2, triple negative subtypes, larger use of chemo±hormonotherapy. At median f-up of 51 months DFS and OS were 84 and 85% respectively in high, 89 and 90% in intermediate, 92 and 94% respectively in low Ki67LI group (p <0.001). There were 456 relapses (12%): 207 (5.4%) in high, 136 (3.6%) in intermediate and 113 (3%) in low Ki67LI group. Using median ki67LI value for different homogenous ER+ grading groups (ER+GG) we stratified these populations in low and high risk. The results are shown in the table. Conclusions: Ki67 LI confirms to be a significant prognostic biomarker for DFS and OS in EBC, associated with other clinical-pathological characteristics. Cutoffs are different into ER+GG. They can cathegorize at least two biological entities in every grading group providing additional prognostic information in planning therapies and outcome prediction