Background: Metastasis is the major cause of breast cancer-related mortality and therefore is the major barrier towards the goal of ending breast cancer. There are only limited treatment options for patients with metastatic breast cancer, most with minor clinical benefits. A major barrier to the effectiveness of these therapies is their inability to target the phenotypic plasticity of metastatic cancer cells. Thus, there is an urgent need to identify new drug targets and develop effective treatment methods. Because epigenetic aberrations contribute significantly to metastasis and are reversible, epigenetic regulators are pharmacologically tractable targets for the treatment of metastatic breast cancer.

Objective/Hypothesis: Our central hypothesis is that epigenetic mechanisms are essential for metastasis progression and can be targeted to prevent and treat metastatic breast cancer. Thus, our vision to end breast cancer is based on systematic analysis of epigenetic mechanisms of metastasis and development of novel epigenetic drugs to prevent and treat metastasis.

Specific Aims: (1) Develop a platform for identification of key epigenetic mechanisms of breast cancer metastasis. (2) Dissect the role of epigenetic regulators of breast cancer metastasis. (3) Develop small molecule modulators of epigenetic regulators of breast cancer metastasis for clinical use.

Study Design: First, we will conduct comprehensive analysis of human patient samples to identify clinically relevant epigenetic mechanisms of metastasis. We will develop a bioinformatics pipeline to incorporate gene expression and epigenomic datasets to systematically pinpoint the epigenetic mechanisms critical for metastasis. Second, we will combine in vivo studies using preclinical mouse models and cell-based mechanistic studies to reveal the contribution of epigenetic mechanisms to various stages of metastasis. Third, we will conduct involve high-throughput screening for small molecules that specifically modulate the identified epigenetic mechanisms and further development of these agents for clinical use. We will then test the lead compounds from our screens and other sources singly and in combination in high-throughput cell-based assays, followed by preclinical testing in animal models.