RESUMO
The transcription factor Snai2, encoded by the SNAI2 gene, is an evolutionarily conserved C2H2 zinc finger protein that orchestrates biological processes critical to tissue development and tumorigenesis. Initially characterized as a prototypical epithelial-to-mesenchymal transition (EMT) transcription factor, Snai2 has been shown more recently to participate in a wider variety of biological processes, including tumor metastasis, stem and/or progenitor cell biology, cellular differentiation, vascular remodeling and DNA damage repair. The main role of Snai2 in controlling such processes involves facilitating the epigenetic regulation of transcriptional programs, and, as such, its dysregulation manifests in developmental defects, disruption of tissue homeostasis, and other disease conditions. Here, we discuss our current understanding of the molecular mechanisms regulating Snai2 expression, abundance and activity. In addition, we outline how these mechanisms contribute to disease phenotypes or how they may impact rational therapeutic targeting of Snai2 dysregulation in human disease.
Assuntos
Fatores de Transcrição da Família Snail/metabolismo , Animais , Epigênese Genética/genética , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Modelos Biológicos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição da Família Snail/genéticaRESUMO
DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but also promote tissue aging. Because mice lacking Slug/Snai2 exhibit limited stem cell activity, including luminobasal differentiation, and are protected from mammary cancer, we reasoned that Slug might regulate DNA damage checkpoints in mammary epithelial cells. Here, we show that Slug facilitates efficient execution of RPA32-mediated DNA damage response (DDR) signaling. Slug deficiency leads to delayed phosphorylation of ataxia telangiectasia mutated and Rad3-related protein (ATR) and its effectors RPA32 and CHK1. This leads to impaired RAD51 recruitment to DNA damage sites and persistence of unresolved DNA damage. In vivo, Slug/Snai2 loss leads to increased DNA damage and premature aging of mammary epithelium. Collectively, our work demonstrates that the mammary stem cell regulator Slug controls DDR checkpoints by dually inhibiting differentiation and facilitating DDR repair, and its loss causes unresolved DNA damage and accelerated aging.
Assuntos
Dano ao DNA , Reparo do DNA , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Humanas/citologia , Fatores de Transcrição da Família Snail/deficiência , Animais , Diferenciação Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Senescência Celular/fisiologia , Células HEK293 , Humanos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismoRESUMO
During the formation of breast cancer, many genes become altered as cells evolve progressively from normal to a pre-malignant to a malignant state of growth. How mutations in genes lead to specific subtypes of human breast cancer is only partially understood. Here we review how initial genetic or epigenetic alterations within mammary epithelial cells (MECs) can alter cell fate decisions and put pre-malignant cells on a path towards cancer development with specific phenotypes. Understanding the early stages of breast cancer initiation and progression and how normal developmental processes are hijacked during transformation has significant implications for improving early detection and prevention of breast cancer. In addition, insights gleaned from this understanding may also be important for developing subtype-specific treatment options.
