Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rar[beta]

We provide experimental evidence that the rare subgroup of triple-negative breast cancer characterized by constitutive activation of the NOTCH1 signaling pathway is sensitive to the anti-tumor action of all-trans retinoic acid, the active metabolite of vitamin A. In this tumor context, all-trans retinoic acid exerts not only an effective action on its own, but it also stimulates the inhibitory activity of y-secretase inhibitors, a series of therapeutic agents targeting NOTCH1, on cancer cell growth. From a basic and mechanistic standpoint, an important result of the study regards the specific involvement of the retinoid receptor RAR(3 in the anti-tumor action exerted by all-trans retinoic acid in sensitive triple-negative breast cancer cells. From an applicative point of view the study represents the basis for the design of clinical trials on the efficacy of combinations between all-trans retinoic acid and y-secretase inhibitors in the treatment of patients affected by a specific subtype of triple-negative breast cancer.