Grant: Operating Grant - Priority Announcement: Breast Cancer

Select breast cancers and certain other cancers are more difficult to treat, resulting in devastating diagnoses. Autocrine motility factor (AMF) and its receptor, Gp78, promote tumor cell motility and metastasis and are linked to malignancy in various cancers. Gp78 is found both at the cell surface, where it internalizes AMF from outside the cell, and also inside the cell in the endoplasmic reticulum, where it targets proteins for degradation. Gp78 is found in regions of the endoplasmic reticulum that interact with mitochondria, the energy producing organelle of the cell, where it breaks down mitochondrial proteins and controls the movement and destruction of mitochondria. Both the endoplasmic reticulum and mitochondria play important roles in cell death. We hypothesize that AMF and Gp78 act at the level of these cellular components to promote the survival of tumor cells leading to tumor progression and malignancy. AMF cleaves HER2 (a cell surface receptor), making tumor cells resistant to treatment with Herceptin, that is currently used to treat HER2-positive breast cancer patients. Intriguingly, Gp78-positive breast cancers are HER2-negative representing a malignant form of breast cancer that is difficult to treat. We will now study how AMF controls Gp78 function in breast cancer and whether AMF control of Gp78 affects its ability to cleave HER2. We made an experimental mouse that expresses elevated levels of Gp78 in breast tissue. We will now generate a mouse that overexpresses AMF in breast tissue and also study mice that lack Gp78. These studies will allow us to determine the relationship between AMF interaction with Gp78 and HER2 and breast cancer development. We are optimistic that our knowledge translation approach to share research results will enable new mechanistic understandings that will lead to new diagnostic and therapeutic approaches to better treat these potentially terminal cancers and provide a more hopeful prognosis for these cancer patients.