Targeting the RXR Pathway for the Prevention of Triple Negative Breast Cancer
Menée à l'aide de modèles murins de tumeurs mammaires, cette étude évalue l'effet d'un traitement par agonistes du récepteur nucléaire X des rétinoïdes (IRX4204 et 9cUAB30) sur le développement des cancers du sein ER- et triple négatif
Prophylactic treatment with selective estrogen receptor modulators (SERMs) and aroma-tase inhibitors (AIs) targeting the nuclear estrogen receptor (ER) can prevent the formation of ER-positive tumors in women at high risk for breast cancer but does not prevent ER-negative and triple-negative subtypes. In this study, we tested whether nuclear retinoid X receptor (RXR) ago-nists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the de-velopment of ER-negative and triple-negative breast cancers (TNBCs). 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 pre-clinical study data support the further evaluation of use of RXR agonists for the prevention of TNBC.
Cancer Prevention Research , article en libre accès, 2025