Strain Promotes Triple Negative Breast Cancer Proliferation and Migration Via VEGFR-2

Triple negative breast cancer (TNBC) has significantly worse outcomes compared to other subtypes. Strains in the tumor microenvironment (TME) generated by cancer-associated fibroblasts (CAFs) can regulate TNBC progression. Recent studies suggest that expression of VEGFR-2 on TNBC is linked to decreased survival, while our prior studies show strains activate VEGFR-2 to drive angiogenesis. We hypothesized that VEGFR-2 on TNBC can be mechanically activated to alter migration and proliferation.

We utilized MDA-MB-231 TNBC cells loaded into the center chamber of a multi-microtissue TME model; opposing side chambers were loaded with CAFs or normal breast fibroblasts (NBFs). A second series of studies utilized magnetic beads to generate strains in the model without secretion of growth factors. Microtissues were analyzed for TNBC migration and proliferation via Ki67 staining.

TNBC cells migrated significantly more towards CAFs compared to NBFs (5×); TME models with magnetic beads showed a 2× increase in migration compared to no strain controls. TNBC cells treated with shRNA against VEGFR-2 demonstrated decreased overall migration but still significantly more towards CAFs vs. NBFs (2×). Proliferation analyses showed strain significantly increased Ki67 in control cells (10%+ vs. 28%+) but not in shVEGFR-2 TNBC (~ 10% all conditions).

These studies demonstrate that strain in the TME drives increased migration and proliferation of TNBC. Loss of VEGFR-2 suppresses migration and growth, even with mechanical stimulation. Therefore, our results suggest that mechanosignaling via VEGFR-2 on TNBC may regulate disease progression and potentially explain failure of anti-VEGFR-2 drugs in breast cancer patients.

The online version contains supplementary material available at 10.1007/s12195-025-00866-x.