Grant: Project Grant

Select breast cancers and certain other cancers are difficult to treat, resulting in devastating prognostic outcomes. Autocrine motility factor (AMF) and its receptor, Gp78 (also known as AMFR), are linked to malignancy in various cancers. However, Gp78 has recently been shown to prevent cancer formation. Gp78 is found both at the cell surface, where it binds and internalizes AMF from outside the cell, and inside the cell in the endoplasmic reticulum, where it targets proteins for degradation. Our work has defined novel mechanisms by which Gp78 and AMF control interaction of the endoplasmic reticulum with mitochondria, the energy producing organelle of the cell. These interactions control the movement and destruction of mitochondria and limit the production by damaged mitochondria of toxic chemicals that contribute to cancer progression. Further, interaction between ER and mitochondria play important roles in cell death. We propose that by preventing Gp78 proximity to mitochondria, AMF controls whether or not Gp78 prevents cancer formation. We will now study how AMF controls Gp78 localization to the mitochondria-associated ER and how it impacts Gp78 function in breast and other cancers, i.e. whether Gp78 prevents tumor formation or rather drives tumor malignancy. Our proposed mechanism of AMF control of Gp78 function in the endoplasmic reticulum is quite novel and suggests that targeting AMF outside the cell will induce Gp78 tumor suppressor activity. Once validated, these studies will lead to the development of specific therapeutics to prevent AMF control of Gp78. We expect our knowledge translation approach will enable new mechanistic understandings leading to new diagnostic and therapeutic approaches to better treat these potentially terminal cancers and provide better prognoses for cancer patients.