Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors

The causes for malignant progression of disseminated tumors and why recurrence rates differ in women with different breast cancer subtypes are unknown. Here, we report novel mechanisms of tumor plasticity that are mandated by microenvironmental factors and demonstrate that recurrence rates are not strictly due to cell intrinsic properties. Specifically, outgrowth of the same population of incipient tumors is accelerated in mice with triple-negative breast cancer (TNBC) relative to those with luminal breast cancer (LBC). Systemic signals provided by overt TNBCs cause formation of a tumor-supportive microenvironment enriched for EGF and IGF-1 at distant indolent tumor sites. Bioavailability of EGF and IGF-1 enhances expression of transcription factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Combinatorial therapy with EGFR and IGF1R inhibitors prevents malignant progression. These results suggest that plasticity and recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for patients with TNBC.