Author/Authors :
Cavazzoni، نويسنده , , Andrea and Bonelli، نويسنده , , Mara A. and Fumarola، نويسنده , , Claudia and La Monica، نويسنده , , Silvia and Airoud، نويسنده , , Kinda and Bertoni، نويسنده , , Ramona and Alfieri، نويسنده , , Roberta R. and Galetti، نويسنده , , Maricla and Tramonti، نويسنده , , Stefano and Galvani، نويسنده , , Elena and Harris، نويسنده , , Adrian L. and Martin، نويسنده , , Lesley-Ann and Andreis، نويسنده , , Daniele and Bottini، نويسنده , , Alberto and Generali، نويسنده , , Daniele and Petronini، نويسنده , , Pier Giorgio، نويسنده ,
Abstract :
Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.
Keywords :
mTOR , breast , Letrozole , Akt , resistance
