RESUMEN
Aromatase inhibitors (AI) have improved the treatment of oestrogen receptor positive (ER+) breast cancer. Despite the efficacy of these agents over 40% of patients relapse with endocrine resistant disease. Here we describe an in vitro model of acquired resistance to long-term oestrogen deprivation (LTED). The LTED cells retain expression of the ER and appear hypersensitive to oestrogen as a result of altered kinase activity. Furthermore analysis of temporal changes in gene expression during the acquisition of resistance highlight growth factor receptor pathways as key mediators of this adaptive process.
Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Estrógenos/metabolismo , Modelos Biológicos , Receptores de Estrógenos/metabolismo , Anastrozol , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis , Línea Celular Tumoral , Resistencia a Antineoplásicos , Estradiol/análogos & derivados , Estradiol/farmacología , Femenino , Fulvestrant , Perfilación de la Expresión Génica , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Nitrilos/uso terapéutico , Posmenopausia , Receptores de Estrógenos/genética , Recurrencia , Triazoles/uso terapéuticoRESUMEN
Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome caused by germline mutation of the gene for the cell-to-cell adhesion protein E-cadherin. The syndrome is dominated by predisposition to the histologically diffuse, poorly differentiated form of gastric cancer. It is not associated with intestinal-type gastric cancer, but families may have an elevated risk of lobular breast cancer. Here, we review the identified families, mutations, and proposed mechanisms by which E-cadherin loss promotes tumorigenesis.
Asunto(s)
Mutación , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Alelos , Deshidrogenasas de Carbohidratos/genética , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , LinajeRESUMEN
Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.