Metastases are responsible for the vast majority of deaths due to breast cancer. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high rates of metastasis and poor prognosis. We are employing patient-derived xenograft (PDX) models of TNBC to identify drivers of metastasis. Tumor samples are obtained from the breast tumors of patients with TNBC and engrafted immediately into the humanized mammary fat pads of immune-compromised mice. Lentiviral transduction was employed to express bioluminescent and fluorescent markers in two independent PDX models of TNBC. Using these models, we demonstrated that human breast tumors are capable of completing all stages of the metastatic cascade in mice, and metastatic lesions are observed in organs normally found in patients with metastatic breast cancer including lung, liver, bone, brain, and lymph nodes. Dynamic and reversible shifts in the epithelial-to-mesenchymal transition (EMT) were observed as tumors metastasized to lung and were re-passaged to recipient mouse mammary fat pads (MFPs). Lung metastases were isolated using bioluminescence imaging and lung metastasis gene expression signatures were generated. Metastasis signatures from two independent PDX models were compared to identify genes that were commonly deregulated in lung metastases relative to corresponding mammary tumors. Comprehensive gain-of-function screens were then conducted in vivo to identify functional drivers of TNBC metastasis. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a metastatic driver in this screen. CEACAM5 mRNA and protein levels were elevated in lung metastases relative to corresponding MFP tumors in mice. In addition, we demonstrated that CEACAM5 expression was upregulated in the lung metastases of breast cancer patients, and its expression inversely correlated with patient survival. Our data indicate that the metastatic function of CEACAM5 is to promote growth of breast tumors in the lung by inducing MET (mesenchymal-to-epithelial transition).

Citation Format: Emily Powell, Jiansu Shao, Hector Picon, Christopher Bristow, Zhongqi Ge, Caitlin Grzeskowiak, Michael Peoples, Frederick Robinson, Sabrina Jeter-Jones, Christopher Schlosberg, Fei Yang, Yun Wu, Ignacio Wistuba, Stacy Moulder, Fraser Symmans, Kenneth Scott, John Edwards, Han Liang, Timothy Heffernan, Helen Piwnica-Worms. A functional genomic screen in vivo identifies CEACAM5 as a clinically relevant driver of breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5172.