Targeting USP13/BMI-1 molecular axis in breast cancer metastasis

About 1 in 8 U.S. women will develop invasive breast cancer. More than 90% breast cancer deaths occur as a result of cancer spreading to the distant organs. Therefore it is paramount important to better understand the molecular mechanisms of metastasis which will potentially lead to the early diagnosis and therapeutic options for the metastatic disease. Recently, we have performed a screening of the impact of 66 human DUB genes on the breast cancer metastatic potential and uncovered USP13 as a critical driver gene in breast cancer metastasis. We further identified one protein BMI-1 to be a target for USP13. Preliminary data support residues C345 and H823 of the USP13 gene could interact with the protein BMI-1. This proposal aims to investigate the in-depth mechanisms on the pathophysiological role of USP13/BMI-1 in breast cancer metastasis and further address their clinical relevance. We propose to elucidate two objectives: (1) Determine the regulation of BMI-1 abundance and function by USP13 in breast cancer metastasis (2) Target the USP13/BMI-1 cascade to inhibit breast cancer metastasis. Our proposal will provide new insights into our understanding of metastatic breast cancers and may lead to new strategies to prevent or treat this lethal condition.