RESUMEN
Robust prognostic gene signatures and therapeutic targets are difficult to derive from expression profiling because of the significant heterogeneity within breast cancer (BC) subtypes. Here, we performed forward genetic screening in mice using Sleeping Beauty transposon mutagenesis to identify candidate BC driver genes in an unbiased manner, using a stabilized N-terminal truncated ß-catenin gene as a sensitizer. We identified 134 mouse susceptibility genes from 129 common insertion sites within 34 mammary tumors. Of these, 126 genes were orthologous to protein-coding genes in the human genome (hereafter, human BC susceptibility genes, hBCSGs), 70% of which are previously reported cancer-associated genes, and â¼16% are known BC suppressor genes. Network analysis revealed a gene hub consisting of E1A binding protein P300 (EP300), CD44 molecule (CD44), neurofibromin (NF1) and phosphatase and tensin homolog (PTEN), which are linked to a significant number of mutated hBCSGs. From our survival prediction analysis of the expression of human BC genes in 2,333 BC cases, we isolated a six-gene-pair classifier that stratifies BC patients with high confidence into prognostically distinct low-, moderate-, and high-risk subgroups. Furthermore, we proposed prognostic classifiers identifying three basal and three claudin-low tumor subgroups. Intriguingly, our hBCSGs are mostly unrelated to cell cycle/mitosis genes and are distinct from the prognostic signatures currently used for stratifying BC patients. Our findings illustrate the strength and validity of integrating functional mutagenesis screens in mice with human cancer transcriptomic data to identify highly prognostic BC subtyping biomarkers.
Asunto(s)
Neoplasias de la Mama/genética , Transformación Celular Neoplásica/genética , Elementos Transponibles de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutagénesis Insercional , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Biología Computacional/métodos , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Ratones , Ratones Noqueados , Mutación , Pronóstico , Reproducibilidad de los Resultados , Riesgo , Transducción de Señal , Análisis de Supervivencia , TranscriptomaRESUMEN
Axonal and dendritic arbors can be characterized statistically by their spatial density function, a function that specifies the probability of finding a branch of a particular arbor at each point in a neural circuit. Based on an analysis of over a thousand arbors from many neuron types in various species, we have discovered an unexpected simplicity in arbor structure: all of the arbors we have examined, both axonal and dendritic, can be described by a Gaussian density function truncated at about two standard deviations. Because all arbors are characterized by density functions with this single functional form, only four parameters are required to specify an arbor's size and shape: the total length of its branches and the standard deviations of the Gaussian in three orthogonal directions. This simplicity in arbor structure can have implications for the developmental wiring of neural circuits.
Asunto(s)
Axones/fisiología , Dendritas/fisiología , Modelos Biológicos , Vías Nerviosas/fisiología , Algoritmos , Animales , Axones/clasificación , Procesos de Crecimiento Celular , Biología Computacional , Dendritas/clasificación , Especificidad de la Especie , Sinapsis/fisiologíaRESUMEN
Lhx1 and Lhx5 are co-expressed in multiple interneuron cell types in the developing spinal cord. These include early-born dI4 and dI6 inhibitory interneurons, as well as late-born inhibitory dILA neurons (dILA), all of which express the paired-domain transcription factor Pax2. Although it appears that Lhx1 and Lhx5 do not control the initial specification of the neuronal cell types in which they are expressed, we have found a cell-autonomous requirement for either Lhx1 or Lhx5 to maintain the expression of Pax2, Pax5 and Pax8 in dorsal inhibitory neurons at later developmental stages. Lhx1; Lhx5 double-knockout mice exhibit a downregulation of Gad1 and Viaat (Slc32a1) from E13.5 onwards that is closely associated with a decrease in Pax2 expression. Pax2 is a key factor for dorsal GABAergic identity, with the expression of Pax5 and Pax8 being differentially dependent on Pax2 in the dorsal horn. In summary, our findings support a model in which the differentiation of GABAergic interneurons in the dorsal cord depends on Pax2, with Lhx1 and Lhx5 helping to activate and maintain Pax2 expression in these cells. Lhx1 and Lhx5 therefore function together with Pax2, Pax5 and Pax8 to establish a GABAergic inhibitory-neurotransmitter program in dorsal horn interneurons.