The Role of MTDH in Mammary Gland Development and the Characterization of the MTDH-SND1 Interaction in Breast Cancer

Abstract

The oncogene Metadherin (MTDH) is frequently amplified and/or overexpressed in >40% of human breast cancers and positively correlates with poor clinical outcome. By generating knockout and transgenic mouse models, a graduate student in our lab had recently shown that Mtdh plays a pivotal role in mammary tumor initiation. However, despite its clinical significance and phenotype, little is actually known about MTDH. Basic molecular information such as its functional domains, its interacting partners, and the signaling pathway in which it functions remain scarce or lacking. And though its association with disease has been well appreciated, there has been little to no effort to understand MTDH’s role in normal development and physiology. Here I thus aim to further our understanding of this mysterious protein and the mechanism by which it functions in breast tumor initiation by contributing some of our first conceptions of its role in normal mammary gland development and morphogenesis, and by characterizing MTDH’s interactions with some of its binding partners. I have demonstrated MTDH’s significance in early mammary gland morphogenesis and its role in the mammary epithelium hierarchy. And, since recent studies have identified staphylococcal nuclease domain-containing protein 1 (SND1), a component of the RNA-Induced Silencing Complex (RISC), to be one of MTDH’s major binding partners, I have also determined the functional significance of the MTDH-SND1 interaction in breast tumorigenesis and dissected the biochemical interaction relationship among MTDH, SND1, and Argonaut 2 (AGO2), the main catalytic component of RISC.