Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice

The transcription factor achaete-scute homologue-1 (ASH1) is essential for neural differentiation during fetal development and is a cardinal feature o f neuroendocrine (NE) tumors such as small cell lung cancer. To explore the potential of ASH1 to promote NE differentiation and tumorigenesis in the l ung, we constitutively expressed the factor in nonendocrine airway epitheli al cells using transgenic mice. Progressive airway hyperplasia and metaplas ia developed beginning at 3 weeks of life. ASH1 potently enhanced the tumor igenic effect of SV40 large T antigen in airway epithelium. These doubly tr ansgenic animals developed massive NE lung tumors, implying that ASH1 may c ooperate with defects in p53, pRb, or related pathways in promoting NE lung carcinogenesis.