Signatures of Breast Cancer Progression in the Blood: What Could Be Learned from Circulating Tumor Cell Transcriptomes

Gene expression profiling has revolutionized our understanding of cancer biology, showing an unprecedented ability to impact patient management especially in breast cancer. The vast majority of breast cancer gene expression signatures derive from the analysis of the tumor bulk, an experimental approach that limits the possibility to dissect breast cancer heterogeneity thoroughly and might miss the message hidden in biologically and clinically relevant cell populations. During disease progression or upon selective pressures, cancer cells undergo continuous transcriptional changes, which inevitably affect tumor heterogeneity, response to therapy and tendency to disseminate. Therefore, metastasis-associated signatures and transcriptome-wide gene expression measurement at single-cell resolution hold great promise for the future of breast cancer clinical care. Seen from this perspective, transcriptomics of circulating tumor cells (CTCs) represent an attractive opportunity to bridge the knowledge gap and develop novel biomarkers. This review summarizes the current state-of-the-science on CTC gene expression analysis in breast cancer, addresses technical and clinical issues related to the application of CTC-derived signatures, and discusses potential research directions.