Single-cell RNA sequencing reveals novel gene expression signatures of trastuzumab treatment in HER2+ breast cancer: A pilot study

摘要

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer accounts for ～20% of invasive breast cancers and is associated with poor prognostics. The recent outcome of HER2+ breast cancer treatment has been vastly improved owing to the application of antibody-targeted therapies. Trastuzumab (Herceptin) is a monoclonal antibody designed to target HER2+ breast cancer cells. In addition to improved survival in the adjuvant treatment of HER2+ breast cancer, trastuzumab treatment has also been associated with cardiotoxicity side effect. However, the molecular mechanisms of trastuzumab action and trastuzumab -mediated cardiotoxicity are still not fully understood. Previous research utilized bulk transcriptomics analysis to study the underlining mechanisms, which relied on averaging molecular signals from bulk tumor samples and might have overlooked key expression features within breast cancer tumor. In contrast to previous research, we compared the single cancer cell level transcriptome profile between trastuzumab -treated and nontreated patients to reveal a more in-depth transcriptome profile . A total of 461 significantly differential expressed genes were identified, including previously defined and novel gene expression signatures. In addition, we found that trastuzumab -enhanced MGP gene expression could be used as prognostics marker for longer patient survival in breast invasive carcinoma patients, and validated our finding using TCGA (The Cancer Genome Atlas) breast cancer dataset. Moreover, our study revealed a 48-gene expression signature that is associated with cell death of cardiomyocytes, which could be used as early biomarkers for trastuzumab -mediated cardiotoxicity . This work is the first study to look at single cell level transcriptome profile of trastuzumab -treated patients, providing a new understanding of the molecular mechanism(s) of trastuzumab action and trastuzumab -induced cardiotoxicity side effects.