PHARMACOLOGICAL INHIBITION OF TFF3 ENHANCES SENSITIVITY-AND OVERCOMES ACQUIRED RESISTANCE-TO DOXORUBICIN IN ESTROGEN RECEPTOR-POSITIVE BREAST CANCER

Abstract

Dose-dependent toxicity and acquired-resistance are two major limitations in the efficacious treatment of breast cancer (BC) with doxorubicin. Here, we investigated the function of Trefoil Factor 3 (TFF3) in the sensitivity of ER+BC to doxorubicin. Doxorubicin treatment of ER+BC increased TFF3 expression. The depletion of TFF3 by siRNA or inhibition with a small molecule TFF3 inhibitor (AMPC) synergistically enhanced the efficacy of doxorubicin in ER+BC through the suppression of doxorubicin-induced AKT activation and enhancement of doxorubicin-induced apoptosis. Using a model of acquired doxorubicin resistance in ER+BC, elevated expression of TFF3 with the hyper-activation of AKT were observed. However, depletion of TFF3 resulted in no significant abrogation of resistance. Despite that, AMPC as a single agent displayed enhanced inhibitory effects on the survival of these resistant cells. Taken together, the addition of TFF3 inhibitors to doxorubicin treatment is a promising strategy to improve treatment efficacy and reduce dose-dependent toxicity of doxorubicin in ER+BC patients. Moreover, inhibiting TFF3 alone may also be a potential approach to eradicate the doxorubicin resistant ER+BC.