Tumor angiogenesis is primarily regulated by
vascular endothelial growth factor and its receptor (
VEGF-VEGFR) communication, which is involved in
cancer cell growth, progression, and
metastasis.
Diindolylmethane (DIM), a dietary bioactive from cruciferous vegetables, has been extensively studied in preclinical models for
breast cancer prevention and treatment. Nevertheless, the possible role of DIM in the angiogenesis and
metastasis regulations in
triple-negative breast cancer (TNBC) remains elusive. Here, we investigated the potential anti-angiogenic and anti-metastatic role of DIM in combination with
centchroman (CC). We observed that the
oral administration of the DIM and CC combination suppressed primary
tumor growth and
tumor-associated vascularization in 4T1
tumors. Further, the DIM and CC combination exhibited a strong inhibitory effect on
VEGF-induced angiogenesis in
matrigel plugs. The mechanistic study demonstrated that DIM and CC could effectively downregulate VEGFA expression in
tumor tissue and strongly interact with VEGFR2 to block its
kinase activity. Interestingly, the DIM and CC combination also suppressed the lung
metastasis of the highly metastatic 4T1
tumors through the downregulation of FAK/MMP9/2 signaling and reversal of epithelial-to-mesenchymal transition (EMT). Overall, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as adjuvant
therapy for treating TNBC.