Molecular Determinants and Clinical Implications of Breast Cancer Dormancy.

摘要

In this award, we have been focusing on the role of cellular dormancy in promoting cancer aggressiveness and drug resistance in recurred breast cancer. We aimed to determine the impact of dormancy on breast cancer phenotype, and to identify the molecular determinants that mediate breast cancer dormancy. During this two-year of grant period, we have successfully established a reliable in vitro breast cancer dormancy cell model. Using this model, we tested and confirmed the hypothesis that we originally proposed in our grant proposal. As what we hypothesized, we found that ER+ but not ER- dormant breast cancer cells repaired double strand DNA breaks likely through the increased activity of the error-prone NHEJ in cells, which led to higher gene mutations and transcriptome reprogramming. After exited from dormancy, these ER+ but not ER- breast cancer cells became more drug-resistant and more malignant compared to the parental cells. More importantly, our work on whole exome sequencing and transcriptome analysis revealed several potential molecules involved in dormancy-mediated recurrence and malignancy which may serve as important diagnosis biomarkers and therapeutic targets for breast cancer recurrence prevention and therapy in the future.