RESUMEN

OBJECTIVE: To investigate the immunohistochemical (IHC) expression of the ErbB/HER family in primary vulvar squamous cell carcinoma (VSCC). METHODS: We analyzed a series of 125 patients who were surgically treated for VSCC from January 1980 to June 2016. All cases had lymph node (LN) staging and 80 had LN metastasis. A tissue microarray was built for epidermal growth factor receptor (EGFR), HER2, HER3, and HER4 IHC staining. RESULTS: In the primary tumor we found positive expressions for EGFR, HER2, HER3, and HER4 in 5%, 0.9%, 0.9%, and 22.8%, respectively. For the LN metastasis, expressions of EGFR and HER4 were positive in 22.2% and 39.1%, respectively. No cases had positive staining for HER2 and HER3 in the LN metastasis. For HER4, positive expression correlated with smaller tumor sizes (P = 0.02). However, positive HER4 was related to adverse prognostic factors such as: histological grade (P = 0.012), presence of lymphovascular space invasion (40.9% vs 16.2%; P = 0.035), and perineural invasion (57.1% vs 16.7%; P = 0.006). Notably, all cases with LN metastasis had positive HER4 in the primary tumor (P < 0.001). ErbB/HER family expression was not related to worse survival. CONCLUSION: EGFR, HER2, and HER3 were infrequently expressed in VSCC by IHC. HER4 IHC expression was found in 22.8% of cases and was related to adverse prognostic factors.

Asunto(s)

Neoplasias de la Vulva , Femenino , Humanos , Inmunohistoquímica , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Receptor ErbB-4/metabolismo

RESUMEN

BACKGROUND: Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides an opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies. OBJECTIVE: To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study. STUDY DESIGN: We developed a polycystic ovary syndrome phenotyping algorithm on the basis of the Rotterdam criteria and applied it to 3 electronic health record-linked biobanks to identify cases and controls for genetic study. In the discovery phase, we performed an individual genome-wide association study using the Geisinger MyCode and the Electronic Medical Records and Genomics cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1×10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed-effect model was adopted for meta-analysis. In addition, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used the STRING database to characterize protein-protein interaction network. RESULTS: Using the same algorithm based on the Rotterdam criteria, we identified 2995 patients with polycystic ovary syndrome and 53,599 population controls in total (2742 cases and 51,438 controls from the discovery phase; 253 cases and 2161 controls in the validation phase). We identified 1 novel genome-wide significant variant rs17186366 (odds ratio [OR]=1.37 [1.23, 1.54], P=2.8×10-8) located near SOD2. In addition, 2 loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42, 2.10], P=5.2×10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52, 2.86], P=8.45×10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 single-nucleotide polymorphisms with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, whereas rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using the STRING database to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1, which has been previously associated with polycystic ovary syndrome. CONCLUSION: Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4 and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome.

Asunto(s)

Síndrome del Ovario Poliquístico/genética , Receptor ErbB-4/genética , Transactivadores/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Estudios de Casos y Controles , Registros Electrónicos de Salud , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Hiperandrogenismo/genética , Infertilidad Femenina/genética , Persona de Mediana Edad , Oligomenorrea/genética , Quistes Ováricos/genética , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/fisiopatología , Polimorfismo de Nucleótido Simple , Superóxido Dismutasa/genética , Factores de Transcripción/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP

RESUMEN

BACKGROUND: The epidermal growth factor receptors participate in the physiological processes such as regulation of morphogenesis, proliferation and cell migration, but when overexpressed or overactivated they may play an important role in neoplastic progression. Melanoma is the most aggressive skin neoplasm and is characterized by elevated invasion and low survival rates in both humans and dogs. In human melanomas the overexpression of EGFR, HER3 or HER4 is associated with poor prognosis. In canine melanomas the epidermal growth factor receptors expression has not been evaluated. Therefore, this study evaluated the expression of epidermal growth factor receptors by immunohistochemistry and investigated their relationship with morphological characteristics and proliferative indices in cutaneous and oral canine melanoma. RESULTS: In cutaneous melanoma an increased proliferative index was associated with increased cytoplasmic HER4 and reduced EGFR and HER3 protein expression. In oral melanomas, membranous HER2 protein expression correlated with occurrence of emboli, but ERBB2 gene amplification wasn't observed. CONCLUSION: Thus, our work evidenced the relationship between HER4 and the stimulus to cell proliferation in cutaneous melanomas, in addition to the relationship between HER2 and the occurrence of emboli in oral melanomas.

Asunto(s)

Receptores ErbB/metabolismo , Melanoma/veterinaria , Neoplasias de la Boca/veterinaria , Animales , Proliferación Celular , Perros , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Inmunohistoquímica/veterinaria , Melanoma/metabolismo , Neoplasias de la Boca/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/veterinaria , Melanoma Cutáneo Maligno

RESUMEN

INTRODUCTION: Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic subtype of breast cancer comprising approximately 0.5% to 5.0% of all invasive breast cancers with a poor prognosis and limited therapeutic options. PATIENTS AND METHODS: We investigated MBC at our institution to evaluate outcomes and investigate the molecular profile of our cohort to determine the presence of mutations for which there are targeted therapies. RESULTS: We found our cohort to consist mainly of the matrix-producing variant (72%) with 48% having the stereotypical estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor-2-negative phenotype. While the overall survival of our cohort was an average of 1679 days (4.6 years), we had a surprising number of patients with second primaries (40%) and distant metastases (40%), yet few recurrences (12%). Molecular analysis of the tumors indicated that one gene mutation, CSFIR, was significantly associated with outcome (P = .021); however, the cohort was defined by frequent mutations in ERBB4 (36%), PIK3CA (48%), and FLT3 (60%), for which there are now targeted therapies. CONCLUSION: While surgery is the appropriate first step in the management of this aggressive malignancy, the collection of data pertaining to the use of targeted agents, although anecdotal, may provide clues to better treatment for these patients.

Asunto(s)

Biomarcadores de Tumor/genética , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/secundario , Metaplasia/patología , Recurrencia Local de Neoplasia/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundario , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Metaplasia/genética , Metaplasia/metabolismo , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Pronóstico , Receptor ErbB-2/metabolismo , Receptor ErbB-4/genética , Receptores del Factor Estimulante de Colonias/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Tirosina Quinasa 3 Similar a fms/genética

RESUMEN

Gastric cancer (GC) is the third leading cause of cancer death worldwide; both environmental and genetic factors are involved in the etiology of this neoplasia. The human epidermal receptor (HER) pathway is essential for proliferation and differentiation of normal cells; but it is also implicated in the growth of cancer cells. In this work we investigate the molecular alterations in genes that encodes for HER receptors reported in GC, as well the role as therapeutic targets. We reviewed the literature reported to date regarding overexpression of HER-receptors, amplification and somatic mutations in ERBB genes occurred in gastric tumors, as well as the anti-HER therapies tested for treatment of GC. In GC, the overexpression of HER family is reported in a range of 12-87% of cases; up to 67% of cases with amplification, and 90 somatic mutations in ERBB genes. The only drug anti-HER approved for using combined with chemotherapy, in treatment of patients with advanced GC is trastuzumab; however, other targeted therapies are being investigated. The role of the HER family as a therapeutic target has not shown significant improvements in recent years; hence, further studies are required to find better options for treatment of GC.

Asunto(s)

Antineoplásicos Inmunológicos/uso terapéutico , Receptores ErbB/genética , Mutación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Genes erbB-2/genética , Humanos , Masculino , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Receptor ErbB-4/genética , Neoplasias Gástricas/metabolismo

RESUMEN

BACKGROUND: Myocardial stretch increases force biphasically: the Frank-Starling mechanism followed by the slow force response (SFR). Based on pharmacological strategies, we proposed that epidermal growth factor (EGF) receptor (EGFR or ErbB1) activation is crucial for SFR development. Pharmacological inhibitors could block ErbB4, a member of the ErbB family present in the adult heart. We aimed to specifically test the role of EGFR activation after stretch, with an interference RNA incorporated into a lentiviral vector (small hairpin RNA [shRNA]-EGFR). METHODS AND RESULTS: Silencing capability of p-shEGFR was assessed in EGFR-GFP transiently transfected HEK293T cells. Four weeks after lentivirus injection into the left ventricular wall of Wistar rats, shRNA-EGFR-injected hearts showed ≈60% reduction of EGFR protein expression compared with shRNA-SCR-injected hearts. ErbB2 and ErbB4 expression did not change. The SFR to stretch evaluated in isolated papillary muscles was ≈130% of initial rapid phase in the shRNA-SCR group, while it was blunted in shRNA-EGFR-expressing muscles. Angiotensin II (Ang II)-dependent Na+/H+ exchanger 1 activation was indirectly evaluated by intracellular pH measurements in bicarbonate-free medium, demonstrating an increase in shRNA-SCR-injected myocardium, an effect not observed in the silenced group. Ang II- or EGF-triggered reactive oxygen species production was significantly reduced in shRNA-EGFR-injected hearts compared with that in the shRNA-SCR group. Chronic lentivirus treatment affected neither the myocardial basal redox state (thiobarbituric acid reactive substances) nor NADPH oxidase activity or expression. Finally, Ang II or EGF triggered a redox-sensitive pathway, leading to p90RSK activation in shRNA-SCR-injected myocardium, an effect that was absent in the shRNA-EGFR group. CONCLUSIONS: Our results provide evidence that specific EGFR activation after myocardial stretch is a key factor in promoting the redox-sensitive kinase activation pathway, leading to SFR development.

Asunto(s)

Receptores ErbB/genética , Corazón/fisiopatología , Miocardio/metabolismo , Angiotensina II/farmacología , Animales , Receptores ErbB/metabolismo , Silenciador del Gen , Proteínas Fluorescentes Verdes , Células HEK293 , Corazón/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Masculino , ARN Interferente Pequeño , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-4/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Vasoconstrictores/farmacología

RESUMEN

ErbB4 is an oncogene belonging to the epidermal growth factor receptor family and contributes to the occurrence and development of multiple cancers, such as gastric, breast, and colorectal cancers. Therefore, studies of the regulation of ErbB4 in cancerigenic pathway will advance molecular targeted therapy. Advanced bioinformatic analysis softwares, such as ExPASy, Predictprotei, QUARK, and I-TASSER, were used to analyze the regulatory mechanism after ErbB4 gene mutation in terms of amino acid sequence, primary, secondary, and tertiary structure of the protein and upstream-downstream receptor/ligands. Mutation of the 19th and 113th amino acids at the carboxyl terminus of ErbB4 protein did not affect its biological nature, but its secondary structure changed and protein binding sites were near 2 mutational sites; moreover, after mutation introduction, additional binding sites were observed. Tertiary structure modeling indicated that local structure of ErbB4 was changed from an α helical conformation into a ß chain folding structure; the α helical conformation is the functional site of protein, while active sites are typically near junctions between helical regions, thus the helical structures are easily destroyed and change into folding structures or other structures after stretching. Mutable sites of ErbB4 is exact binding sites where dimer formed with other epidermal growth factor family proteins; mutation enabled the ErbB4 receptor to bind to neuregulin 1 ligand without dimer formation, disrupting the signal transduction pathway and affecting ErbB4 function.

Asunto(s)

Modelos Genéticos , Mutación , Receptor ErbB-4/genética , Secuencia de Aminoácidos , Biología Computacional/métodos , Humanos , Modelos Moleculares , Neoplasias/genética , Neoplasias/metabolismo , Fosforilación , Unión Proteica , Estructura Secundaria de Proteína , Receptor ErbB-4/química , Receptor ErbB-4/metabolismo , Transducción de Señal , Relación Estructura-Actividad

RESUMEN

Obesity reduces breastfeeding success and lactation performance in women. However, the mechanisms involved are not entirely understood. In the present study, female C57BL/6 mice were chronically exposed to a high-fat diet to induce obesity and subsequently exhibited impaired offspring viability (only 15% survival rate), milk production (33% reduction), mammopoiesis (one-third of the glandular area compared to control animals) and postpartum maternal behaviors (higher latency to retrieving and grouping the pups). Reproductive experience attenuated these defects. Diet-induced obese mice exhibited high basal pSTAT5 levels in the mammary tissue and hypothalamus, and an acute prolactin stimulus was unable to further increase pSTAT5 levels above basal levels. In contrast, genetically obese leptin-deficient females showed normal prolactin responsiveness. Additionally, we identified the expression of leptin receptors specifically in basal/myoepithelial cells of the mouse mammary gland. Finally, high-fat diet females exhibited altered mRNA levels of ERBB4 and NRG1, suggesting that obesity may involve disturbances to mammary gland paracrine circuits that are critical in the control of luminal progenitor function and lactation. In summary, our findings indicate that high leptin levels are a possible cause of the peripheral and central prolactin resistance observed in obese mice which leads to impaired lactation performance.

Asunto(s)

Lactancia/fisiología , Leptina/metabolismo , Glándulas Mamarias Animales/metabolismo , Obesidad/metabolismo , Prolactina/metabolismo , Animales , Dieta Alta en Grasa , Femenino , Hipotálamo/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Neurregulina-1/genética , ARN Mensajero/biosíntesis , Receptor ErbB-4/genética , Factor de Transcripción STAT5/metabolismo

RESUMEN

Previously, we studied the erythroblastic leukemia viral oncogene homolog (erbB) family of tyrosine kinase growth factor receptors in terms of protein expression, modulation and activation in the 3T3-L1 cell line. In the present study, the presence of full-length erbB mRNAs, and splice or proteolytic erbB variants, was evaluated using RT-PCR. Epidermal growth factor receptor (EGFR)/erbB1 expression was confirmed. Wild-type (wt) ErbB2, human erbB2 (HER2)-extracellular domain (ECD) and herstatin mRNA expression were analyzed. Restriction analysis confirmed wt expression. 3T3-L1 cells exhibited HER2-ECD and herstatin mRNA expression, although at extremely low levels (compared to the control cell lines). ErbB3 cDNA was amplified using mouse mammary tumors and rat acines as positive controls. ErbB4 was not positively identified in these cells. In conclusion, this study demonstrates that 3T3-L1 cells express EGFR/erbB1, erbB2 and erbB3, and possibly, certain erbB2 splice or proteolytic variants, which are worth pursuing.

Asunto(s)

Adipocitos/metabolismo , Empalme Alternativo/genética , Receptores de Factores de Crecimiento/genética , Receptores de Factores de Crecimiento/metabolismo , Células 3T3-L1 , Animales , Proliferación Celular , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Receptor ErbB-4

RESUMEN

PURPOSE: The human epidermal growth factor receptor (HER) family consists of four members: ErbB-1 (HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4). These receptors activate numerous downstream pathways in response to extracellular ligands, regulating diverse processes that include differentiation, migration, proliferation, and survival. Alterations in these genes play a role in the development and progression of many human cancers. In gastric carcinomas (GCs), expression of HER1 and HER2 is thought to be a prognostic factor and target of novel biologic agents. The effect of HER3 or HER4 expression in GC has not been sufficiently studied. In this study, we explored the gene and protein expression of the HER family in GC to establish new potential prognostic factors. PATIENTS AND METHODS: Immunohistochemistry and fluorescence in situ hybridization were performed in 221 patients with GC using tissue microarray. Correlation between the expression or amplification of HER genes and the clinicopathologic parameters was statistically analyzed. RESULTS: Alterations of members of the HER family were significantly associated with the parameters involved in tumor progression, including depth of tumor invasion, involved lymph nodes, and tumor stage. In addition, HER2 amplification and HER3 expression were significantly related to worse survival. CONCLUSION: These results reveal that all members of the HER family are expressed in GC. Furthermore, expression of HER2 and HER3 is a significant predictor of poor survival in GC. Therefore, the development of HER-targeted agents and agents targeting downstream signaling pathways provides new possibilities in the treatment of GC.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/mortalidad , Carcinoma/secundario , Carcinoma/terapia , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Multimerización de Proteína , Receptor ErbB-4 , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Resultado del Tratamiento

RESUMEN

SUMMARY: Overexpression of ErbB receptors is frequent in head and neck squamous cell carcinomas (HNSCC) and seems to be correlated with tumor progression and metastasis. Fatty acid synthase (FASN), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, is regulated by ErbB2 and overexpressed in several human malignancies. METHODS: This study was performed to examine the immunohistochemical expression patterns of ErbB1, ErbB2, ErbB3, ErbB4, and FASN in a tissue microarray, containing 33 representative areas from aggressive primary HNSCC (whose patients had distant metastasis), and 21 matched lung metastasis. RESULTS: Strong correlation among the expression of ErbB family receptors was found (ErbB1-ErbB2 P = 0.008, ErbB1-ErbB4 P = 0.018, EbB2-ErbB3 P = 0.001, ErbB2-ErbB4 P = 0.006, ErbB3-ErbB4 P=0.012) in the HNSCC. FASN expression was significantly associated with ErbB2 (P = 0.024). Lymphatic permeation was correlated with ErbB3 (P = 0.033) and histological grade with ErbB4 staining (P = 0.050). ErbB1 and ErbB2 were found mainly in patients with smoking habit (P = 0.011 and P = 0.027), and ErbB2 was associated with alcohol consumption and clinical stage (P = 0.014 and P = 0.031). Finally, FASN was overexpressed in lung metastasis, in comparison with matched HNSCC samples (P = 0.006). CONCLUSIONS: The results showed that high FASN immunohistochemical expression is a feature of HNSCC lung metastasis, and ErbB1-ErbB2, ErbB1-ErbB4, ErbB2-ErbB3, ErbB2-ErbB4, and ErbB3-ErbB4 expression levels are correlated in the respective primary tumors, being ErbB2 the preferred coexpression partner of all the other ErbB receptors.

Asunto(s)

Carcinoma de Células Escamosas/patología , Receptores ErbB/análisis , Acido Graso Sintasa Tipo I/análisis , Neoplasias de Cabeza y Cuello/patología , Adulto , Anciano , Consumo de Bebidas Alcohólicas , Carcinoma de Células Escamosas/secundario , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/secundario , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor ErbB-2/análisis , Receptor ErbB-3/análisis , Receptor ErbB-4 , Estudios Retrospectivos , Fumar , Tasa de Supervivencia

RESUMEN

PURPOSE: Investigate ErbB family expression in colorectal cancer patients with higher risk of recurrence after surgical treatment. METHODS: We studied 109 individuals with high risk stage II and stage III patients submitted to radical surgery. ErbB expression was assessed by tissue microarray technique. RESULTS: The immunohistochemical expression was considered positive for EGFR, ErbB2, ErbB3, ErbB4 membrane, and ErbB4 cytoplasmic in respectively 57.8%, 8.3%, 69.7%, 11%, and 19.3% of patients. ErbB3 negative expression was associated with lymphovascular invasion. EGFR, ErbB2, and cytoplasmic ErbB4 expression was not associated with prognosis. Membranous positive ErbB4 expression was an independent prognostic factor for recurrence. ErbB3 negative expression was an independent prognostic factor for recurrence and survival in the multivariate analysis. CONCLUSIONS: The immunohistochemical expression of ErbB3 and ErbB4 may identify a subgroup with stage II and III colorectal cancer at higher risk of recurrence.

Asunto(s)

Neoplasias Colorrectales/patología , Procedimientos Quirúrgicos del Sistema Digestivo , Receptores ErbB/análisis , Anciano , Neoplasias Colorrectales/cirugía , Citoplasma/química , Femenino , Humanos , Inmunohistoquímica , Vasos Linfáticos/patología , Masculino , Proteínas de la Membrana/análisis , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/análisis , Receptor ErbB-3/análisis , Receptor ErbB-4 , Recurrencia , Riesgo

RESUMEN

The mitogenic signaling in mammalian cells is carried out mainly by growth factors that interact with receptors localized at the plasma membrane. Most of these receptors have a tyrosine kinase activity domain that is localized at the cytoplasmic region of the molecule. The interaction of the growth factors with the receptors, besides inducing the kinase activity of the receptor, activate signaling pathways the alter gene expression patterns and induce mitogenesis, or if deregulated are related to cancer. Among these receptors ERBB, VEGF, PDGF and IGF are attractive targets for directed therapies. ERBB receptors are frequently involved in the production of many types of cancers. Both, the over-expression of the growth factor and the receptor, besides mutations at the cytoplasmic tyrosine kinase domain contribute to constitutive signaling in human cancer. VEGF has a pivotal role in maintaining the tumor growth by facilitating growth of new blood vessels. Therefore, inhibition of tumor growth targeting of the tumor vasculature, by interfering with the activity of VEGFr is now a real alternative in combinatorial therapies. PDGF is a growth factor involved in growth of connective tissue and wound healing. Activating mutations of PDGFr have been found in gastrointestinal tumors and the autocrine signaling maintained by this receptor have been described in many tumors. Imatinib, and inhibitor of the tyrosine kinase activity of Bcr-Abl targets also the kinase of the PDGFr. Finally IGF-I an II have an important antiapoptotic and pro-mitogenic role in most tumors. Different inhibitors are now under clinical studies for the use in combination of chemotherapeutic drugs in the treatment of different tumors.

Asunto(s)

Sustancias de Crecimiento/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Transducción de Señal , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/fisiología , Genes erbB , Genes erbB-1 , Genes erbB-2 , Humanos , Ligandos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/fisiopatología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/fisiopatología , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Factor de Crecimiento Derivado de Plaquetas/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/fisiología , Receptor ErbB-3/antagonistas & inhibidores , Receptor ErbB-3/fisiología , Receptor ErbB-4 , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/fisiología , Transducción de Señal/fisiología , Somatomedinas/antagonistas & inhibidores , Somatomedinas/fisiología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/fisiología

RESUMEN

INTRODUCTION: CNS metastases mean a great challenge. It has been suggested that the brain metastases incidence could be high in metastasic breast cancer patients receiving trastuzumab based-therapies. MATERIAL AND METHODS: We performed a descriptive analysis of our experience in this setting. 86 patients met the criteria (From Oct/99 to Oct/03). RESULTS: CNS progression occurred in 17 patients (19.5%). Mean age of CNS progression disease patients was 45.4 years while mean age for all the patients was 50.5 years. Response rate for the entire group of patients was: OR 39.7%; CB (OR + SD) 69%. Response rate to trastuzumab based-therapy was OR 82.4% and CB 88.2 at the time of CNS progression. Median time from the start of trastuzumab therapy up to the CNS progression was 10 months. OS was 23.4 weeks. CONCLUSIONS: The incidence of CNS involvement is high in young metastasic breast cancer women responding to trastuzumab-based therapies. This may lead to prophylactic cranial irradiation strategies or to the early detection in asymptomatic patients to improve surgery or radiosurgery results in these patients.

Asunto(s)

Adenocarcinoma/secundario , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/secundario , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Adulto , Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Carcinoma/química , Carcinoma/tratamiento farmacológico , Carcinoma/epidemiología , Irradiación Craneana , Progresión de la Enfermedad , Receptores ErbB/análisis , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/antagonistas & inhibidores , Receptor ErbB-4 , Estudios Retrospectivos , Análisis de Supervivencia , Trastuzumab , Resultado del Tratamiento

RESUMEN

Exposure of cultured cerebellar granule neurons (24 h serum-starved) during 3 min to 30% hyposmotic medium activated the tyrosine kinase receptor ErbB4 in the absence of its ligand. Hyposmolarity also activated the non-receptor tyrosine kinases, Src, focal adhesion kinase (FAK), extracellular signal-regulated protein kinase (ERK)1/2, and the tyrosine kinase target phosphatidyl-inositol-3-kinase (PI3K). The hyposmotic-induced activation of these kinases required the prior phosphorylation of ErbB4 as shown by the effect of ErbB4 blockade with AG213 reducing by 85-95% the phosphorylation of FAK and ERK1/2, by 74% and 36% that of PI3K and Src, respectively. These results suggest a key role of ErbB4 as a signal integrator of events associated with hyposmolarity. PI3K seems to be an important connecting element in the signaling network evoked by the hyposmolarity/ErbB4 activation as: (i) the p85 regulatory subunit of PI3K co-immunoprecipitates with ErbB4 and with FAK; (ii) PI3K blockade with wortmannin reduced the hyposmotic activation of FAK (90%) and ERK1/2 (84-91%). Inhibition of Src with PP2 reduced ErbB4 phosphorylation and inhibited the subsequent cytosolic kinase activation with the same potency as ErbB4 blockade. These results point to Src and ErbB4 and as early targets of the hyposmotic stimulus and osmosignaling. The functional significance for cell volume regulation of the ErbB4-Src-PI3K signaling cascade is indicated by the 48-66% decrease of the hyposmotic taurine efflux observed by inhibition of these kinases.

Asunto(s)

Cerebelo/metabolismo , Receptores ErbB/metabolismo , Neuronas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Células Cultivadas , Cerebelo/citología , Cerebelo/enzimología , Medios de Cultivo/farmacología , Activación Enzimática , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Adhesiones Focales/fisiología , Concentración Osmolar , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Receptor ErbB-4 , Taurina/metabolismo , Factores de Tiempo , Familia-src Quinasas/metabolismo

RESUMEN

The neuregulin receptor tyrosine kinase Erb-b4, initially linked to early cardiac development, is shown here to play a critical role in adult cardiac function. In wild-type mice, Erb-b4 protein localized to Z lines and to intercalated disks, suggesting a role in subcellular and intercellular communications of cardiomyocytes. Conditional inactivation of erb-b4 in ventricular muscle cells led to a severe dilated cardiomyopathy, characterized by thinned ventricular walls with eccentric hypertrophy, reduced contractility, and delayed conduction. This cardiac dysfunction may account for premature death in adult erb-b4-knockout mice. This study establishes a critical role for Erb-b4 in the maintenance of normal postnatal cardiac structure and function.

Asunto(s)

Cardiomiopatía Dilatada/fisiopatología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Animales , Cardiomegalia/genética , Cardiomegalia/fisiopatología , Cardiomiopatía Dilatada/genética , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Contracción Miocárdica , Miocardio/metabolismo , Miocardio/patología , Receptor ErbB-4 , Transducción de Señal

RESUMEN

Implantation is a crucial event in human pregnancy. The participation of cytokines in the implantation process has been widely documented, although the role of many of these molecules is still a matter of controversy. In a previous report from our laboratory, we demonstrated that addition of interferon-gamma to the culture medium produces deleterious effects on mouse embryo development. In this study we investigated the effect of this cytokine on outgrowing embryo morphology and on the expression of epidermal growth factor receptors (ErbBs) and heparan sulfate proteoglycan (perlecan) in mouse embryos cultured in vitro. Morphological assessment of inner cell mass and trophoblast development was carried on in-situ fixed and stained outgrowths. Localization of ErbB1, ErbB4 and perlecan on pre- and peri-implantation embryos was investigated by immunocytochemistry. Addition of interferon-gamma produced a deleterious effect on both inner cell mass and trophoblast morphology. Immunostaining demonstrated that ErbB1, ErbB4 and perlecan are present on pre-implantation embryos and blastocysts; interferon-gamma altered the expression of ErbB4 and Perlecan at the blastocyst stage. We propose that the effects produced by this cytokine could be related to the altered acquisition of adhesion competence and low implantation rates observed in certain reproductive immunological disorders.

Asunto(s)

Blastocisto/fisiología , Desarrollo Embrionario/efectos de los fármacos , Interferón gamma/farmacología , Animales , Blastocisto/química , Receptores ErbB/análisis , Femenino , Proteoglicanos de Heparán Sulfato/análisis , Inmunohistoquímica/métodos , Ratones , Receptor ErbB-4 , Proteínas Recombinantes , Técnicas de Cultivo de Tejidos , Trofoblastos/fisiología

RESUMEN

Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGbeta1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGbeta1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGbeta1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGbeta1 action indicated that the addition of HRGbeta1 to LM3 cells resulted in activation of phosphatidylinositol 3- kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGbeta1 also caused the rapid activation of ERK1/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGbeta1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEK1/ERKs activity with PD98059, resulted in suppression of the ability of HRGbeta1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGbeta1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGbeta1-induced proliferation appear to be distinct from those involved in HRGbeta1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.

Asunto(s)

Neoplasias Mamarias Animales/patología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neurregulina-1/metabolismo , Neurregulina-1/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Western Blotting , División Celular , Movimiento Celular , Dimerización , Relación Dosis-Respuesta a Droga , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Receptores ErbB/metabolismo , Flavonoides/farmacología , Regulación de la Expresión Génica , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Metástasis de la Neoplasia , Fenotipo , Fosforilación , Pruebas de Precipitina , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Receptor ErbB-4 , Ribonucleasas/metabolismo , Transducción de Señal , Factores de Tiempo , Células Tumorales Cultivadas