Isthmin-1 is a newly identified extracellular matrix protein which has been shown to be widely expressed and is critical for Nodal signaling (Osorio et al. J cell Biol. 2019).The Isthmin-1 transgenic and knockout mice have been generated to investigate its role in development and diseases. Loss of Isthmin-1 impairs mammary gland development with much less branching morphogenesis. In addition, loss of Isthmin-1 reduces tumor umber and tumor burden in breast cancer mouse model, suggesting a key role for Isthmin-1 in breast cancer development. We will take various approaches to investigate underlying mechanisms for Isthmin-1 in regulating tumor development and branching morphogenesis.