Dietary Diindolylmethane Enhances the Therapeutic Effect of Centchroman in Breast Cancer by Inhibiting Neoangiogenesis.

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.