The Apocrine Profile of Triple-negative Breast Carcinomas in Patients Aged 45 Years or Younger: favorable but rare features / Perfil apócrino em carcinomas mamários triplonegativos de pacientes até 45 anos: característica favorável, ainda que rara

Abstract Objective Triple-negative breast carcinomas (TNBCs) represent a heterogeneous group of neoplasias, even though they generally exhibit a clinically more aggressive phenotype, and are more prevalent in young women. To date, targeted therapies for this group of tumors have not been defined. The aim of this study was to evaluate the frequency of the apocrine subtype in TBNCs from premenopausal patients as defined by the immunohistochemical expression of the androgen receptor (AR) and its association with: histological type; tumor grade; proliferative activity; epidermal growth factor receptor (EGFR) expression; and a basal-like phenotype. Methods A total of 118 tumor samples from patients aged 45 years or younger were selected and reviewed according to histological type and grade. Ki-67 expression was also evaluated. Immunohistochemical expression of the AR, basal cytokeratin ⅚, and EGFR expression were analyzed in tissue microarrays. The apocrine subset was defined by AR-positive expression. The basal-like phenotype was characterized by cytokeratin ⅚ and/or EGFR expression. Results An apocrine profile was identified in 6/118 (5.1%) cases. This subset of cases also exhibited a lower rate of Ki-67 expression (17.5% versus 70.0%, p= 0.02), and a trend toward a lower histological grade (66.7% versus 27.9%, p= 0.06). Conclusions The apocrine subtype of TNBCs is rare among premenopausal women, and it tends to present as carcinomas of lower grade and lower proliferative activity, suggesting a less aggressive biological phenotype.

Resumo Objetivo Carcinomas mamários triplo-negativos representam um grupo heterogêneo de neoplasias, embora geralmente exibam fenótipo clinicamente mais agressivo e sejam mais prevalentes em mulheres jovens. Até o presente, terapias-alvo para esses grupos não foram definidas. O objetivo deste estudo foi avaliar a frequência do subtipo apócrino em carcinomas mamários triplo-negativos de mulheres na pré-menopausa, definido pela expressão imuno-histoquímica do receptor de androgênio, e sua associação com tipo histológico, grau histológico, atividade proliferativa, expressão do receptor do fator de crescimento epidérmico (EGFR) e o fenótipo basal-símile. Métodos Foram selecionadas 118 amostras de tecido tumoral de pacientes com até 45 anos de idade. As amostras foram revisadas quanto a tipo e grau histológicos e expressão do Ki-67. A expressão imuno-histoquímica de receptor de androgênio, citoqueratina basal ⅚, e do EGFR foram analisadas em amostras de microarranjos de tecido. O subtipo apócrino foi definido pela positividade do receptor de androgênio. O fenótipo basal-símile foi caracterizado pela expressão da citoqueratina ⅚ e/ou do EGFR. Resultados O perfil apócrino foi identificado em 6/118 (5,1%) casos. Este subgrupo apresentou menor fração de expressão do Ki-67 (17,5% versus 70,0%, p= 0,02) e uma tendência a menor grau histológico (66,7% versus 27,9%, p= 0,06). Conclusões O subtipo apócrino dos carcinomas mamários triplo-negativos é raro em mulheres na pré-menopausa, e tende a se apresentar como carcinomas de menor grau e menor atividade proliferativa, sugerindo fenótipo biológico menos agressivo.

Evaluation of P53, E-cadherin, Cox-2, and EGFR protein imunnoexpression on prognostic of resected gallbladder carcinoma / Avaliação da imuno-expressão das proteínas P53, E-caderina, Cox-2 e EGFR no prognóstico do carcinoma de vesícula biliar ressecado

BACKGROUND: Gallbladder carcinoma presents a dismal prognosis. Choice treatment is surgical resection that is associated a high levels of both morbidity and mortality. Best knowledgement of prognostic factors may result a better selection of patients either for surgical or multimodal treatment. AIM: To evaluate tecidual immunoexpression of P53, E-cadherin, Cox-2, and EGFR proteins and to correlate these findings with resected gallbladder adenocarcinoma survival. METHODS: Clinical, laboratorial, surgical, and anatomopathological reports of a series of gallbladder adenocarcinoma patients were collected by individualized questionary. Total sample was 42 patients. Median of age was 72 years (35-87). There were seven men and 35 women. Lesion distribuition in according TNM state was the following: T1 (n=2), T2 (n=5), T3 (n=31), T4 (n=4). Twenty-three patients underwent radical resection (R0), while 19 palliative surgery (R1-R2). A block of tissue microarray with neoplasic tissue of each patient was confected. It was performed evaluation of P53, E-Caderine, COX-2, and EGFR proteins imunoexpression. These findings were correlated with overall survival. RESULTS: Five-year survival was 28%. The median of global survival was eight months. Only immunoexpression of EGFR protein was considered independent variable at multivariated analysis. CONCLUSION: Final prognosis was influenced by over-expression of EGFR protein in tumoral tissue. .

RACIONAL: O carcinoma de vesícula biliar apresenta mau prognóstico. O tratamento de escolha é a ressecção cirúrgica que está associado à alta morbimortalidade. O melhor conhecimento de fatores prognósticos pode resultar em melhor seleção dos doentes para o tratamento cirúrgico e multimodal. OBJETIVOS: Avaliar a imunoexpressão tecidual das proteínas P53, E-caderina, Cox-2 e EGFR e correlacionar com a sobrevida do adenocarcinoma de vesícula biliar ressecado. MÉTODO: Os dados clínicos, laboratoriais, cirúrgicos e anatomopatológicos de uma série de doentes operados por adenocarcinoma de vesicula biliar foram coletados. A casuística total foi de 42 doentes. A mediana de idade foi de 72 anos (35-87). Foram sete homens e 35 mulheres. A distribuição da lesão de acordo com TNM foi a seguinte: T1 (n=2), T2 (n=5), T3 (n=31), T4 (n=4). Vinte três doentes realizaram ressecção radical (R0) enquanto 19 operação paliativa (R1-R2). Um bloco de tissue microarray foi confeccionado com tecido neoplásico de cada doente. para avaliação da imunoexpressão das proteínas P53, E-Caderina, COX-2 e EGFR. Esses achados foram correlacionados com prognóstico final dos doentes. RESULTADOS: A sobrevida estimada em cinco anos foi de 28%. A mediana de sobrevida global foi de oito meses. Apenas a imunoexpressão da proteína EGFR foi considerada variável independente no prognóstico dos doentes. CONCLUSÃO: Pior prognóstico teve relação com a imunoexpressão aumentada da proteína EGFR no tecido tumoral. .

EGFR and KRAS Mutations in Patients With Adenocarcinoma of the Lung

BACKGROUND/AIMS: Mutations of the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) are important in the pathogenesis of lung cancer, and recent reports have revealed racial and geographical differences in mutation expression. METHODS: This study was conducted to investigate the prevalence of EGFR and KRAS mutations and their correlation with clinical variables in Korean patients with adenocarcinoma of the lung. Formalin-fixed adenocarcinoma specimens from 104 randomly selected patients diagnosed at Kosin University Gospel Hospital from October 1996 to January 2005 were used for the study. RESULTS: We found a high prevalence of EGFR mutations and a low prevalence of KRAS mutations. EGFR mutations were present in 24% (25 of 104) of the samples: one mutation in exon 18, 13 in exon 19, one in exon 20, and 10 in exon 21. The presence of an EGFR mutation was not associated with gender, smoking history, histological grade, age, bronchioalveolar components, or cancer stage in patients with adenocarcinoma of the lung. CONCLUSIONS: Mutations of KRAS were present in 9.6% (9 of 94) of the samples: eight in codon 12 and one in codon 13. EGFR mutations were never found in tumors with KRAS mutations, suggesting a mutually exclusive relationship.

A função do óxido nítrico no processo de angiogênese através do controle da atividade do receptor EGF / A critical role for NO-mediated, epidermal growth factor receptor-dependent angiogenesis in endothelial cells

Óxido nítrico (NO) obtido a partir de fonts exógenas estimula a via de sinalização Ras/MAP cinases ERK1/2 em células endoteliais de coelho (RAEC). A ativação desta via também envolve a transativação do receptor de EGF (EGFR) mediada por ERK1/2 (Oliveira, 2003). Agora, nós avaliamos os efeitos de NO gerado endogenamente por bradicinina e "shear stress" sobre a fosforilação de resíduos de tirosina em EGFR e no processo de angiogênese; Nós encontramos que após estímulo com bradicinina (1 ´MU´M) ou "shear stress" (16 dynes/cm2) a isoforma endotelial de NO sintetase (eNOS) foi ativada em células RAEC e HUVEC. Além disso, o aumento na produção de NO correlaciona-se com um aumento fosforilação em resíduos de tirosina de EGFR conforme verificado por imunoprecipitação e western blot. Para determinar a capacidade angiogênica da via de sinalização NO-EGFR, nós usamos um ensaio in vitro baseado em Matrigel®. Em adição nós analisamos as vias de sinalização envolvidas no processo. Nós mostramos que bradicina e "shear stress" induz a formação de estruturas semelhantes a capilares em células HUVEC cultivadas em Matrigel®. Células HUVEC expressando um mutante de EGFR com atividade de tirosina cinase defective não forma estruturas semelhantes a capilares após estímulo com bradicinina ou "shear stress". Reunidos, estes achados nos sugerem que a ativação da via de NO e EGFR é necessária na promoção de angiogênese em células HUVEC...

Overexpression of c-erbB-2 oncoprotein and associated pathobiological factors in invasive primary breast cancer.

Breast cancer tissues from 271 cases were analyzed immunologically for c-erbB-2 oncoprotein (HER-2/neu), epidermal growth factor receptor (EGF-R) and estrogen receptor (ER). Overexpression of both c-erbB-2 oncoprotein and EGF-R showed an inverse association with ER and a direct association with metastatic involvement of lymph node and high histological grade. The frequency of c-erbB-2 and EGF-R overexpression was significantly higher among postmenopausal cases in comparison with premenopausal cases. Further, only in postmenopausal patients, c-erbB-2 oncoprotein (chi2 = 6.4, P < 0.05) and EGF-R (chi2 = 6.4, p < 0.05) as well as their concomitant expression (chi2 = 11.5, p < 0.01) revealed a statistically significant association with ER.

The mechanism of c-erbB-2 gene product increase in stomach cancer cell lines

c-erbB-2 oncogene encodes a growth factor receptor whose amino acid sequence has extensive homology with human epidermal growth factor receptor. It is frequently overexpressed in human breast, ovary, lung, and stomach cancers, where its overexpression is related significantly to the prognosis. Tl investigate the possible role of c-erbB-2 oncogene in the oncogenesis of stomach cancer, we examined the genetic alterations of c-erbB-2 oncogene in 4 stomach cancer cell lines, SNU-1, SNU-5, SNU-16 and KATO III. There were no differences in c-erbB-2 mRNA level as well as c-erbB-2 gene copy number among them. But gp185-erbB-2, c-erbB-2 gene product, was increased from 2- to 4-fold in SNU-1 and SNU-5 cells, compared with that in SNU-16 or KATO III cells. Our results suggest that post-transcriptional regulation of gp185erbB-2 expression may underlie gp185erbB-2 overexpression in cancer cells.

Maturation and externalization of EGF-receptor: a cell-surface located oncoprotein.

The EGF-receptor is a proto-oncogene encoded membrane protein related to the verb-B oncogene product of avian erythroblastosis virus. Here we report studies on expression and maturation characteristics of this receptor. The expression of intact 170 kDa EGF-receptor as well as a 100 kDa homologue that contains only the external domain is enhanced by the ligand EGF. EGF acts at transcriptional and post-transcriptional levels. To dissociate these pre-translational effects and the effects of EGF on receptor polypeptide synthesis from those on receptor export, pulse-chase experiments were conducted. These studies indicate that EGF stimulates post-translational transport and processing of the receptor, and this stimulation can occur in the absence of new protein synthesis. Other studies show that EGF accelerates at least two slow events in receptor maturation--the deoxynojirimycin-sensitive processing in endoplasmic reticulum (ER) and the swainsonine-sensitive processing in golgi, suggesting that EGF may influence one or more of the rate determining steps that control receptor export from ER. Overall the results demonstrate that EGF controls EGF-receptor expression at multiple levels, viz. at transcriptional, pre-translational and post-translational pathways of receptor biosynthesis.