RESUMO
N-cadherin and HER2/neu were found to be co-expressed in invasive breast carcinomas. To test the contribution of N-cadherin and HER2 in mammary tumor metastasis, we targeted N-cadherin expression in the mammary epithelium of the MMTV-Neu mouse. In the context of ErbB2/Neu, N-cadherin stimulated carcinoma cell invasion, proliferation and metastasis. N-cadherin caused fibroblast growth factor receptor (FGFR) upmodulation, resulting in epithelial-to-mesenchymal transition (EMT) and stem/progenitor like properties, involving Snail and Slug upregulation, mammosphere formation and aldehyde dehydrogenase activity. N-cadherin potentiation of the FGFR stimulated extracellular signal regulated kinase (ERK) and protein kinase B (AKT) phosphorylation resulting in differential effects on metastasis. Although ERK inhibition suppressed cyclin D1 expression, cell proliferation and stem/progenitor cell properties, it did not affect invasion or EMT. Conversely, AKT inhibition suppressed invasion through Akt 2 attenuation, and EMT through Snail inhibition, but had no effect on cyclin D1 expression, cell proliferation or mammosphere formation. These findings suggest N-cadherin/FGFR has a pivotal role in promoting metastasis through differential regulation of ERK and AKT, and underscore the potential for targeting the FGFR in advanced ErbB2-amplified breast tumors.
Assuntos
Neoplasias da Mama/patologia , Caderinas/genética , Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Aldeído Desidrogenase/biossíntese , Animais , Benzamidas/farmacologia , Caderinas/biossíntese , Movimento Celular/genética , Proliferação de Células , Ciclina D1/biossíntese , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Transição Epitelial-Mesenquimal/genética , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Humanos , Neoplasias Pulmonares/secundário , MAP Quinase Quinase 1/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/biossíntese , Transdução de Sinais/genética , Fatores de Transcrição da Família Snail , Esferoides Celulares/patologia , Células-Tronco/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/biossíntese , Células Tumorais CultivadasRESUMO
The metabolically active and redox-active mitochondrion appears to play a major role in the cellular metabolism of the transition metal, iron. Frataxin, a mitochondrial matrix protein, has been identified as playing a key role in the iron metabolism of this organelle due to its iron-binding properties and is known to be essential for iron-sulphur cluster formation. However, the precise function of frataxin remains elusive. The decrease in frataxin expression, as seen in the inherited disorder Friedreich's ataxia, markedly alters cellular and mitochondrial iron metabolism in both the mitochondrion and the cell. The resulting dysregulation of iron trafficking damages affects tissues leading to neuro- and cardiodegeneration. This disease underscores the importance of iron homeostasis in the redox-active environment of the mitochondrion and the molecular players involved. Unravelling the mechanisms of altered iron metabolism in Friedreich's ataxia will help elucidate a biochemical function for frataxin. Consequently, this will enable the development of more effective and rationally designed treatments. This review will focus on the emerging function of frataxin in relation to the observed alterations in mitochondrial iron metabolism in Friedreich's ataxia. Tissue-specific alterations due to frataxin loss will also be discussed, as well as current and emerging therapeutic strategies.
