Restriction and characterization of human breast cancer using a three-dimensional embryonic stem cell model

摘要

Human breast cancer is currently the highest diagnosed form of cancer and the second leading cause of cancer-related deaths in American women. Triple negative breast cancer is of the basal subtype and displays the worst prognosis owing to its highly metastatic properties. Current treatments focused on eradicating breast tumors in lieu of or following local therapy include chemotherapy, hormonal therapy, and targeted therapy. Hormonal therapy is not an option for triple negative breast cancer as it does not contain hormone receptors and there are currently no approved biological targeted therapies. Chemotherapy has proven unsuccessful because triple negative breast cancer is highly drug resistant. Here we report that metastatic human breast cancer cells (BCCs) were converted to a less aggressive phenotype and overcame chemotherapeutic drug resistance following exposure to embryonic stem cells (ESCs) encapsulated in alginate microstrands. We also demonstrate that the 3D ESC model restores proper EGFR and canonical Wnt/beta-catenin signaling pathway regulation in metastatic BCCs and can be applied to identify a biological treatment for triple negative breast cancer. This study establishes the feasibility of inhibiting highly aggressive human BCCs with 3D cultured ESCs as demonstrated through decreases in metastatic BCC proliferation, abnormal metabolism, migration, invasiveness, chemotherapeutic drug resistance, and survival in vitro. ESCs and BCCs display signaling pathway convergence, which is highly and precisely regulated in ESCs and dysregulated in BCCs. Gene expression at the mRNA and protein level within restricted human BCCs indicates inhibition of the oncogenic EGFR and canonical Wnt/beta-catenin signaling pathways. Naked cuticle 2 (NKD2) is a potential point of cross-talk between these two pathways and its increased expression suggests a role in restored regulation of these pathways. Application of this model for mechanistic studies will enable development of a targeted treatment for triple negative human breast cancer.