RESUMO
Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation - similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 - stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation - similar to those found in tumours bearing endogenous Kras2 mutations - induce cellular senescence that is Ink4a-Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53-Ink4a-Arf-dependent senescence checkpoints.
Assuntos
Transformação Celular Neoplásica/metabolismo , Senescência Celular , Células Epiteliais/metabolismo , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Proteína Oncogênica p21(ras)/metabolismo , Lesões Pré-Cancerosas/metabolismo , Fatores de Ribosilação do ADP/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Doxiciclina/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Hiperplasia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Mutação , Proteína Oncogênica p21(ras)/genética , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Transporte Proteico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismo , Regulação para CimaRESUMO
Breast cancer recurrence is a fundamental clinical manifestation of tumor progression and represents the principal cause of death from this disease. Using a conditional transgenic mouse model for the recurrence of HER2/neu-induced mammary tumors, we demonstrate that the transcriptional repressor Snail is spontaneously upregulated in recurrent tumors in vivo and that recurrence is accompanied by epithelial-to-mesenchymal transition (EMT). Consistent with a causal role for Snail in these processes, we show that Snail is sufficient to induce EMT in primary tumor cells, that Snail is sufficient to promote mammary tumor recurrence in vivo, and that high levels of Snail predict decreased relapse-free survival in women with breast cancer. In aggregate, our observations strongly implicate Snail in the process of breast cancer recurrence.
Assuntos
Neoplasias Mamárias Experimentais/genética , Recidiva Local de Neoplasia/genética , Fatores de Transcrição/genética , Animais , Neoplasias da Mama/genética , Células Epiteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Mamárias Experimentais/patologia , Mesoderma/patologia , Camundongos , Camundongos Transgênicos , Recidiva Local de Neoplasia/patologia , Receptor ErbB-2/genética , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismoRESUMO
To determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state.
