Grant: Operating Grant - Priority Announcement: Breast Cancer

Autocrine motility factor (AMF) and its receptor, Gp78, promote tumor cell motility and metastasis and are closely associated with malignancy in various cancers. Curiously, Gp78 is found both at the cell surface where it internalizes AMF from outside the cell and inside the cell, within the endoplasmic reticulum, where it targets proteins for degradation. Gp78 is localized to regions of the endoplasmic reticulum that interact closely with mitochondria. We have shown that Gp78 degrades mitochondrial proteins and controls the movement and destruction of mitochondria. Both these cellular organelles play important roles in cell death and we hypothesize that AMF and Gp78 act at these sites to promote tumor cell survival and thereby tumor progression and malignancy. We will now study how AMF regulates Gp78 function in breast cancer. Recent data has shown that AMF cleaves the cell surface receptor HER2, rendering tumor cells resistant to treatment with the clinical therapeutic agent trastuzumab (Herceptin) that is currently used in the clinic to treat breast cancer patients with HER2 positive tumors. Intriguingly, Gp78-positive breast cancers are HER2-negative and the relationship between AMF regulation of tumor cell survival through Gp78 and its ability to cleave HER2 remains unknown. We have generated a transgenic mouse that expresses Gp78 in mammary tissue and found that Gp78 overexpression increases mammary cell proliferation. We will now generate a mouse overexpressing AMF in mammary tissue and also study mice that lack Gp78. These studies will allow us to determine the relationship between AMF interaction with Gp78 and HERs and breast cancer progression. We will also actively develop new therapeutics that might both inhibit AMF regulation of Gp78 and its ability to cleave HER2, potentially developing novel therapeutics that may enhance the efficacy of trastuzumab for the treatment of breast cancer.