Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer

<p>Abstract</p> <p>Background</p> <p>The biological relevance of nuclear ErbB-2/HER2 (NuclErbB-2) presence in breast tumors remains unexplored. In this study we assessed the clinical significance of ErbB-2 nuclear localization in primary invasive breast cancer. The reporting recommendations for tumor marker prognostic studies (REMARK) guidelines were used as reference.</p> <p>Methods</p> <p>Tissue microarrays from a cohort of 273 primary invasive breast carcinomas from women living in Chile, a Latin American country, were examined for membrane (MembErbB-2) and NuclErbB-2 expression by an immunofluorescence (IF) protocol we developed. ErbB-2 expression was also evaluated by immunohistochemistry (IHC) with a series of antibodies. Correlation between NuclErbB-2 and MembErbB-2, and between NuclErbB-2 and clinicopathological characteristics of tumors was studied. The prognostic value of NuclErbB-2 in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore NuclErbB-2 as independent prognostic factor for OS.</p> <p>Results</p> <p>The IF protocol we developed showed significantly higher sensitivity for detection of NuclErbB-2 than IHC procedures, while its specificity and sensitivity to detect MembErbB-2 were comparable to those of IHC procedures. We found 33.6% NuclErbB-2 positivity, 14.2% MembErbB-2 overexpression by IF, and 13.0% MembErbB-2 prevalence by IHC in our cohort. We identified NuclErbB-2 positivity as a significant independent predictor of worse OS in patients with MembErbB-2 overexpression. NuclErbB-2 was also a biomarker of lower OS in tumors that overexpress MembErbB-2 and lack steroid hormone receptors.</p> <p>Conclusions</p> <p>We revealed a novel role for NuclErbB-2 as an independent prognostic factor of poor clinical outcome in MembErbB-2-positive breast tumors. Our work indicates that patients presenting NuclErbB-2 may need new therapeutic strategies involving specific blockage of ErbB-2 nuclear migration.</p

Progesterone receptor activation downregulates GATA3 by transcriptional repression and increased protein turnover promoting breast tumor growth

The transcription factor GATA3 is involved in mammary gland development and is crucial for the maintenance of the differentiated status of luminal epithelial cells. The role of GATA3 in breast cancer as a tumor suppressor has been established, although insights into the mechanism of GATA3 expression loss are still required.Fil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Mercogliano, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Tkach, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Inurrigarro, Gloria. Sanatorio Mater Dei Hermanas de María de Schoenstatt; ArgentinaFil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Cerchietti, Leandro. Weill Cornell Medical College; Estados UnidosFil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Activation of Stat3 by Heregulin/ErbB-2 through the Co-Option of Progesterone Receptor Signaling Drives Breast Cancer Growth▿ †

Cross talk between the steroid hormone receptors for estrogen and progesterone (PR) and the ErbB family of receptor tyrosine kinases appears to be a hallmark of breast cancer growth, but its underlying mechanism remains poorly explored. Here we have highlighted signal transducer and activator of transcription 3 (Stat3) as a key protein activated by heregulin (HRG), a ligand of the ErbB receptors, through co-opted, ligand-independent PR function as a signaling molecule. Stat3 activation was an absolute requirement in HRG-induced mammary tumor growth, and targeting Stat3 effectively inhibited growth of breast cancer cells with activated HRG/ErbB-2 and PR. Our findings unravel a novel potential therapeutic intervention in PR- and ErbB-2-positive breast tumors, involving the specific blockage of PR signaling activity

Heregulin Co-opts PR transcriptional action via Stat3 role as a coregulator to drive cancer growth

Accumulated findings have demonstrated the presence of bidirectional interactions betweenprogesterone receptor (PR) and the ErbB family of receptor tyrosine kinases signaling pathways inbreast cancer. We previously revealed signal transducer and activator of transcription 3 (Stat3) asa nodal convergence point between said signaling pathways proving that Stat3 is activated by oneof the ErbBs? ligands, heregulin (HRG)1 via ErbB2 and through the co-option of PR as a signalingmolecule. Here, we found that HRG1 induced Stat3 recruitment to the promoters of the progestin-regulatedcell cycle modulators Bcl-XL and p21CIP1 and also stimulated Stat3 binding to themouse mammary tumor virus promoter, which carries consensus progesterone response elements.Interestingly, HRG1-activated Stat3 displayed differential functions on PR activity depending onthe promoter bound. Indeed, Stat3 was required for PR binding in bcl-X, p21CIP1, and c-mycpromoters while exerting a PR coactivator function on the mouse mammary tumor virus promoter.Stat3 also proved to be necessary for HRG1-induced in vivo tumor growth. Our resultsendow Stat3 a novel function as a coregulator of HRG1-activated PR to promote breast cancergrowth. These findings underscore the importance of understanding the complex interactionsbetween PR and other regulatory factors, such as Stat3, that contribute to determine the contextdependenttranscriptional actions of PR. (MoFil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Cordo Russo, Rosalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: de Martino, Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pineda, Viviana. Universidad de la Frontera. Departamento de Anatomía Patológica; ChileFil: Muñoz, Sergio. Universidad de la Frontera. Departamento de Anatomía Patológica; ChileFil: Guzman, Pablo. Universidad de la Frontera. Departamento de Anatomía Patológica; ChileFil: Roa, Juan C.. Universidad de la Frontera. Departamento de Anatomía Patológica; Chile. Pontificia Universidad Católica de Chile. Departamento de Anatomía Patológica; Chile. Pontificia Universidad Católica de Chile. Advanced Center for Chronic Diseases; ChileFil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

Fruit, yield, and vegetative growth responses to photosynthetically active radiation during oil synthesis in olive trees

Maximizing productivity in super high density and intensive olive orchards requires proper management of illumination of the canopy walls and their interior. Currently, this is difficult to achieve due to the limited knowledge about the responses to incident photosynthetically active radiation (PAR) of yield determinants and components. We determined the response functions for PAR during the oil synthesis phase of yield components (fruit dry weight and oil concentration) of fruit at a height of  2 m on the canopy periphery by applying several radiation levels (3, 20, 40, and 70% of incident PAR) to the north side (S hemisphere) of well-illuminated trees. The experiment was initiated after endocarp hardening as fruit number had already been established at that time. This avoided possible confounding effects due compensation between fruit number and size. Absence of differential fruit fall in response to treatments and of changes in (endocarp + seed) dry weight after application of treatment confirmed the achievement of this objective. Fruit dry weight, oil concentration, and, consequently, yield increased linearly with mean daily PAR receipt up to a threshold of 15 mol PAR m-2 d-1 (i.e., 40% of PAR). In treatments with irradiance levels below this threshold the fruit became the priority sinks for assimilates, although their growth rate and oil concentration were reduced. Increments in length of non-fruiting branches and of trunk cross-sectional areas were substantially reduced in response to shading. We conclude that manipulation of PAR levels during the oil synthesis phase can reduce final fruit dry weight and oil concentration, confirms the existence of upper thresholds to PAR responses for these variables, and provides evidence that fruit growth has priority in the partitioning of photosynthate over vegetative growth under low to moderate levels of PAR.       Fil: Cherbiy Hoffmann, Silvana Ursula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Regional de Investigaciones Cientificas y Transferencia Tecnológica de Anillaco; ArgentinaFil: Hall, Antonio Juan. Universidad de Buenos Aires. Facultad de Agronomia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Rousseaux, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Regional de Investigaciones Cientificas y Transferencia Tecnológica de Anillaco; Argentin