High VEGFR3 Expression Reduces Doxorubicin Efficacy in Triple-Negative Breast Cancer

Due to the lack of specific targets, cytotoxic chemotherapy still represents the common standard treatment for triple-negative breast patients. Despite the harmful effect of chemotherapy on tumor cells, there is evidence that treatment could modulate the tumor microenvironment in a way favoring the propagation of the tumor. In addition, the lymphangiogenesis process and its factors could be involved in this counter-therapeutic event. In our study, we have evaluated the expression of the main lymphangiogenic receptor VEGFR3 in two triple-negative breast cancer in vitro models, resistant or not to doxorubicin treatment. The expression of the receptor, at mRNA and protein levels, was higher in doxorubicin-resistant cells than in parental cells. In addition, we confirmed the upregulation of VEGFR3 levels after a short treatment with doxorubicin. Furthermore, VEGFR3 silencing reduced cell proliferation and migration capacities in both cell lines. Interestingly, high VEGFR3 expression was significantly positively correlated with worse survival in patients treated with chemotherapy. Furthermore, we have found that patients with high expression of VEGFR3 present shorter relapse-free survival than patients with low levels of the receptor. In conclusion, elevated VEGFR3 levels correlate with poor survival in patients and with reduced doxorubicin treatment efficacy in vitro. Our results suggest that the levels of this receptor could be a potential marker of meager doxorubicin response. Consequently, our results suggest that the combination of chemotherapy and VEGFR3 blockage could be a potentially useful therapeutic strategy for the treatment of triple-negative breast cancer.

Automated summary

Due to the lack of specific targets, cytotoxic chemotherapy remains the standard treatment for triple-negative breast cancer. However, chemotherapy not only affects tumor cells but also modulates the tumor microenvironment in a way that favors tumor propagation. In this study, we found that the expression of the lymphangiogenic receptor VEGFR3 was higher in doxorubicin-resistant cells compared to parental cells. VEGFR3 silencing reduced cell proliferation and migration in both cell lines, and high VEGFR3 expression was associated with worse survival in chemotherapy-treated patients. Our results suggest that targeting VEGFR3 in combination with chemotherapy could be a potential therapeutic strategy for triple-negative breast cancer.