miR-21 Plays a Dual Role in Tumor Formation and Cytotoxic Response in Breast Tumors

SIMPLE SUMMARY: miR-21 is an oncogenic microRNA that has been associated with breast tumor growth and metastasis in vitro and is also noted to be upregulated by cytotoxic stressors in model systems and in breast cancer patients who have undergone radiation. In the present study, our findings demonstrate the novel role of miR-21 in vivo for breast cancer initiation and metastases, and in sensitizing tumor cells to cytotoxic therapy by upregulating the FAS/FASL signaling pathway. ABSTRACT: Breast cancer (BrCa) relies on specific microRNAs to drive disease progression. Oncogenic miR-21 is upregulated in many cancers, including BrCa, and is associated with poor survival and treatment resistance. We sought to determine the role of miR-21 in BrCa tumor initiation, progression and treatment response. In a triple-negative BrCa model, radiation exposure increased miR-21 in both primary tumor and metastases. In vitro, miR-21 knockdown decreased survival in all BrCa subtypes in the presence of radiation. The role of miR-21 in BrCa initiation was evaluated by implanting wild-type miR-21 BrCa cells into genetically engineered mouse models where miR-21 was intact, heterozygous or globally ablated. Tumors were unable to grow in the mammary fat pads of miR-21(−/−) mice, and grew in ~50% of miR-21(+/−) and 100% in miR-21(+/+) mice. The contribution of miR-21 to progression and metastases was tested by crossing miR-21(−/−) mice with mice that spontaneously develop BrCa. The global ablation of miR-21 significantly decreased the tumorigenesis and metastases of BrCa, while sensitizing tumors to radio- and chemotherapeutic agents via Fas/FasL-dependent apoptosis. Therefore, targeting miR-21 alone or in combination with various radio or cytotoxic therapies may represent novel and efficacious therapeutic modalities for the future treatment of BrCa patients.