RESUMEN
AIMS: The utility of p53 as a prognostic assay has been elusive. The aims of this study were to describe a novel, reproducible scoring system and assess the relationship between differential p53 immunohistochemistry (IHC) expression patterns, TP53 mutation status and patient outcomes in breast cancer. METHODS AND RESULTS: Tissue microarrays were used to study p53 IHC expression patterns: expression was defined as extreme positive (EP), extreme negative (EN), and non-extreme (NE; intermediate patterns). Overall survival (OS) was used to define patient outcome. A representative subgroup (n = 30) showing the various p53 immunophenotypes was analysed for TP53 hotspot mutation status (exons 4-9). Extreme expression of any type occurred in 176 of 288 (61%) cases. As compared with NE expression, EP expression was significantly associated (P = 0.039) with poorer OS. In addition, as compared with NE expression, EN expression was associated (P = 0.059) with poorer OS. Combining cases showing either EP or EN expression better predicted OS than either pattern alone (P = 0.028). This combination immunophenotype was significant in univariate but not multivariate analysis. In subgroup analysis, six substitution exon mutations were detected, all corresponding to extreme IHC phenotypes. Five missense mutations corresponded to EP staining, and the nonsense mutation corresponded to EN staining. No mutations were detected in the NE group. CONCLUSIONS: Patients with extreme p53 IHC expression have a worse OS than those with NE expression. Accounting for EN as well as EP expression improves the prognostic impact. Extreme expression positively correlates with nodal stage and histological grade, and negatively with hormone receptor status. Extreme expression may relate to specific mutational status.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Genes p53 , Humanos , Inmunohistoquímica , Inmunofenotipificación/métodos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mutación , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Reproducibilidad de los Resultados , Estudios Retrospectivos , Análisis de Matrices Tisulares , Proteína p53 Supresora de Tumor/genéticaRESUMEN
OBJECTIVES: We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and clinical outcome following platinum and platinum/taxane chemotherapy in sporadic epithelial ovarian cancer (EOC). METHODS: BRCA1 IHC was performed on a cohort of 292 ovarian tumours from two UK oncology centres. BRCA1 protein expression levels were correlated with overall survival (OS), progression free survival (PFS) and clinical response to chemotherapy by multivariate analysis. RESULTS: EOC patients with absent/low BRCA1 protein expression (41%) had a better chance of clinical response following chemotherapy as compared to patients with high BRCA1 expression (odds ratio 2.47: 95%CI 1.10-5.55, p=0.029). Patients with absent/low BRCA1 had a higher probability of clinical response following single agent platinum compared to high BRCA1 expressing patients (68.5% vs. 46.8%), while addition of a taxane increased response rates independent of BRCA1. Overall, patients with absent/low BRCA1 had a better clinical outcome compared to patients with high BRCA1 protein expression in terms of both OS (HR=0.65: 95%CI 0.48-0.88, p=0.006) and PFS (HR=0.74, 95%CI 0.55-0.98, p=0.040). CONCLUSIONS: We confirm that absent/low BRCA1 protein expression is a favourable prognostic marker. However, we also provide the first evidence that absent/low BRCA1 protein expression in sporadic EOC patients predicts for an improved clinical response to chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/genética , Biomarcadores de Tumor/genética , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Compuestos Organoplatinos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Proteína BRCA1/biosíntesis , Biomarcadores de Tumor/biosíntesis , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Carcinoma Epitelial de Ovario , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Glandulares y Epiteliales/metabolismo , Compuestos Organoplatinos/administración & dosificación , Neoplasias Ováricas/metabolismo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tasa de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
Evidence is accumulating to suggest that some of the diverse functions associated with BRCA1 may relate to its ability to transcriptionally regulate key downstream target genes. Here, we identify S100A7 (psoriasin), S100A8, and S100A9, members of the S100A family of calcium-binding proteins, as novel BRCA1-repressed targets. We show that functional BRCA1 is required for repression of these family members and that a BRCA1 disease-associated mutation abrogates BRCA1-mediated repression of psoriasin. Furthermore, we show that BRCA1 and c-Myc form a complex on the psoriasin promoter and that BRCA1-mediated repression of psoriasin is dependent on functional c-Myc. Finally, we show that psoriasin expression is induced by the topoisomerase IIalpha poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent. Therefore, we identified a novel transcriptional mechanism that is likely to contribute to BRCA1-mediated resistance to etoposide.
Asunto(s)
Proteína BRCA1/metabolismo , Neoplasias de la Mama/metabolismo , Proteínas de Unión al Calcio/antagonistas & inhibidores , Proteínas de Unión al Calcio/biosíntesis , Proteínas Proto-Oncogénicas c-myc/metabolismo , Antineoplásicos Fitogénicos/farmacología , Proteína BRCA1/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas de Unión al Calcio/genética , Línea Celular Tumoral , Daño del ADN , Resistencia a Antineoplásicos , Etopósido/farmacología , Regulación Neoplásica de la Expresión Génica , Genes BRCA1 , Humanos , Proteínas Proto-Oncogénicas c-myc/genética , ARN Interferente Pequeño/genética , Proteína A7 de Unión a Calcio de la Familia S100 , Proteínas S100 , Transcripción Genética , TransfecciónAsunto(s)
Sulfato de Bario/análisis , Enfermedades de la Mama/diagnóstico , Mama/patología , Calcinosis/diagnóstico , Medios de Contraste/análisis , Cuerpos Extraños/diagnóstico , Sulfato de Bario/efectos adversos , Enfermedades de la Mama/diagnóstico por imagen , Enfermedades de la Mama/patología , Neoplasias de la Mama/diagnóstico , Calcinosis/diagnóstico por imagen , Calcinosis/etiología , Medios de Contraste/efectos adversos , Diagnóstico Diferencial , Femenino , Cuerpos Extraños/diagnóstico por imagen , Cuerpos Extraños/etiología , Cuerpos Extraños/patología , Humanos , Microscopía Electrónica de Rastreo , Persona de Mediana Edad , RadiografíaAsunto(s)
Neoplasias de la Mama/patología , Carcinoma Adenoide Quístico/patología , Neoplasias Cutáneas/patología , Anciano , Neoplasias de la Mama/diagnóstico , Carcinoma Adenoide Quístico/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/patología , Neoplasias Cutáneas/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
The hyaluronan receptor CD44 plays an important role in facilitating invasion and metastasis of a variety of tumors, including breast carcinomas. CD44 functions as a bioactive signaling transmitter. Although a number of studies have implicated CD44 in breast tumor invasion, the evidence is still circumstantial. We have developed a tetracycline-regulated CD44s (standard form) system in the weakly metastatic breast cancer cell MCF7, which exhibits low endogenous expression of CD44 and generated a new cell line, MCF7F-B5. Induction of CD44s alone affected the growth characteristics of MCF7F-B5 cells by increasing their abilities to proliferate, migrate, and invade in vitro. In addition, we have identified and validated cortactin as a novel transcriptional target of hyaluronan/CD44s signaling in underpinning breast tumor invasion. To test these observations in vivo, we developed a doxycycline (DOX)-regulated CD44s breast cancer xenograft model. Induction of CD44s did not affect the growth rate or local invasion of the primary tumor. However, although no mice from the +DOX group developed metastasis, 8 of 11 mice from the -DOX group developed secondary tumors to the liver only. Interestingly, metastatic breast tumors expressed high levels of CD44. This study provides in vivo evidence for the role of the standard form of CD44 in promoting breast tumor invasion and metastasis to the liver.