Reverse engineering of triple-negative breast cancer cells for targeted treatment

摘要

Highlights ? Currently, there is no targeted treatment available for triple-negative breast cancer. ? Anti-HER2 treatment significantly improves the prognosis of HER2-positive breast cancer. ? Reverse engineering of triple-negative breast cancer to HER2-positive disease might offer a treatment strategy. ? This study showed that triple-negative breast cancer cells reverse engineered to HER2-positive cells are sensitive to anti-HER2 treatment. Abstract Objective Targeting the human epidermal growth factor receptor HER2 has increased survival in HER2-positive breast cancer patients. In the contrast, for triple-negative breast cancer (TNBC) patients, no targeted agents are available. We hypothesized that artificial overexpression of HER2 in TNBC cells might induce sensitivity to anti-HER2 agents in these cells. Methods TNBC cell lines were transduced using lentiviral HER2 overexpression particles. Functionality of HER2 was determined by protein analysis and localization studies. The tumorigenic potential of HER2 overexpressing cells was assessed by analysis of proliferation, migration and invasion capacity. Response to chemotherapeutic agents and anti-HER2 agents was determined by cell viability assays. Results We demonstrated functional overexpression of HER2 in TNBC cell lines of different subtypes. Whereas in cell types with more pronounced epithelial features (e.g. MDA-MB-468) HER2 overexpression increases proliferation and migration, in mesenchymal cell lines (MDA-MB-231 and BT-549) HER2 was able to further increase invasive potential. No changes were found in cancer stem cell characteristics or in response to chemotherapy, a trait of TNBC. When treated with anti-HER2 agents, however, HER2 overexpressing TNBC cells showed increased sensitivity to these agents. Conclusion This proof-of-principle study demonstrates that reverse engineering of TNBC cells might offer a novel targeted treatment strategy for this most aggressive subtype of breast cancer.