Targeting the RXR Pathway for the Prevention of Triple-Negative Breast Cancer.

Prophylactic treatment with selective estrogen receptor (ER) modulators and aromatase inhibitors targeting the nuclear ER can prevent the formation of ER-positive tumors in women at high risk of breast cancer but does not prevent ER-negative and triple-negative subtypes. In this study, we tested whether nuclear retinoid X receptor (RXR) agonists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the development of ER-negative and triple-negative breast cancers. Our study demonstrates that IRX4204 significantly delays the formation of mammary tumors in three ER-negative mouse models: MMTV-ErbB2, C3(1)/SV40-TAg, and Brca1-deficient with modest toxicities. In some of the MMTV-ErbB2 mice, IRX4204 completely prevented mammary tumor formation, and 60% of the IRX4204-treated Brca1-deficient mice remained tumor-free when all vehicle-treated mice had formed tumors. 9cUAB30 treatment also delays tumor formation in Brca1-deficient mice, albeit to a lesser extent. Biomarker analysis revealed that delayed tumors arising after IRX4204 treatment had decreased Ki-67 expression and increased infiltration of cytotoxic T cells. Our preclinical study data support the further evaluation of use of RXR agonists for the prevention of triple-negative breast cancer. Treatment with the RXR agonist IRX4204 significantly delays tumor formation and increases CD8-positive T-cell infiltration in ER-negative murine breast cancer models. This suggests that immune modulation may be critical for rexinoid-based prevention of ER-negative mammary tumors and supports their use in future breast cancer prevention trials for high-risk individuals. See related Spotlight, p. 133.