Abstract P6-04-20: Proteogenomic analysis of estrogen modulated breast cancer metastasis

Abstract

Abstract Background: Estrogen Receptor (ER) positive breast cancer is the most common subtype (70%) and associated with the most deaths from the disease. Almost all deaths from breast cancer are caused by metastasis. While metastatic ER-positive breast cancer is a leading cause of cancer-related death, metastasis studies have largely focused on ER-negative breast cancer. A major reason for such imbalance is the lack of physiologically relevant mice models for studying ER-positive breast cancer. The patient derived xenograft (PDX) technique provides us with a powerful means to study highly clinically relevant human ER-positive breast cancer in mice, but most studies using PDX models still focus on orthotopic rather than metastatic tumor growth. Here we describe studies of the metastatic process using PDX models to more comprehensively understand the value of these PDX lines for therapeutic modelling. These findings will empower us to develop therapeutics designed to control systemic disease, not just orthotopic tumor growth. Experimental design and methods: We have studied 14 ER positive PDX lines in ovariectomized SCID beige mice with and without estradiol supplementation. We have analyzed both orthotopic tumor and a variety of metastatic sites including liver, lung, brain and bone. Data is being generated using next-generation DNA and RNA sequencing, mass spectrometry-based proteomics. We use integrated bioinformatics pipelines to shed light on the metastatic process. Results: We have generated macro-metastatic maps that record sites with observable metastatic nodules of each PDX line in mice. IHC of Liver, bone, brain, lung of each mouse also generated micro-metastatic maps. The most common organ of metastasis in mice is the lung. In some PDX lines, the sites of metastasis differ between groups with and without estradiol supply. The ongoing proteogenomic profiling of orthotopic and metastatic tumors reveals potential molecular drivers of metastasis in ER+ breast cancer. Conclusion: Here, we describe an approach to the systematic investigation of the ER+ breast cancer metastasis process. This approach will allow us to identify druggable targets that may interrupt the metastatic process and/or inhibit tumor growth at metastatic sites. Citation Format: Anran Chen, Purba Singh, Beom-Jun Kim, Lacey E Dobrolecki, Alana L Welm, Michael T Lewis, Matthew J Ellis. Proteogenomic analysis of estrogen modulated breast cancer metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-20.