Development and Cancer: The role of Twisted Gastrulation in mammary gland development and in cancer.

Abstract

It is becoming increasingly clear that the molecular mechanisms that maintain and promote pluripotency during development reemerge as important mediators of tumorigenicity. Bone morphogenetic proteins (BMPs) and their modulators play numerous and diverse roles during development and, as recent evidence suggests, in cancer. One key modulator of BMP signaling during craniofacial and mammary gland development is the glycoprotein Twisted gastrulation-1 (TWSG1). The loss of Twsg1 results in craniofacial malformations, a delay in mammary gland development and lactation defects. TWSG1 has been shown to function both in the positive and negative regulation of BMP signaling. This dual nature may be explained first by TWSG1's ability to bind BMPs and prevent their interaction with receptors. This function is similar to other extracellular BMP antagonists such as Noggin and Gremlin. Additionally, the TWSG1: BMP ligand complex can be joined by Chordin and when this tripartite complex is formed Tolloid can cleave Chordin releasing BMPs into the extracellular space at some concentration. The timing of this release and availability of other extracellular partners may, in part, dictate the influence TWSG1 has on BMP signaling. Interestingly, TWSG1 overexpression has been detected in tumors of tissues in which it also plays a key role in development such as the oral cavity and breast. It therefore provides an interesting model by which to investigate the tenuous balance between pluripotency and tumorigenesis.