Abstract
Dose-dependent toxicity and acquired resistance are two major challenges limiting the efficacious treatment of mammary carcinoma (MC) with doxorubicin. Herein, we investigated the function of Trefoil Factor 3 (TFF3) in the sensitivity and acquired resistance of estrogen receptor positive (ER+) MC cells to doxorubicin. Doxorubicin treatment of ER+MC cells 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+MC through the suppression of doxorubicin-induced AKT activation and enhancement of doxorubicin-induced apoptosis. Elevated expression of TFF3 and increased activation of AKT were also observed using a model of acquired doxorubicin resistance in ER+MC cells. AMPC partially re-sensitized the doxorubicin resistant cells to doxorubicin-induced apoptosis. Indeed, doxorubicin resistant ER + MC cells exhibited increased sensitivity to AMPC as a single agent compared to doxorubicin sensitive cells. In vivo, AMPC attenuated growth of doxorubicin sensitive ER+MC xenografts whereas it produced regression of xenografts generated by doxorubicin resistant ER+MC cells. Hence, TFF3 inhibition may improve the efficacy and reduce required doses of doxorubicin in ER+MC. Moreover, inhibition of TFF3 may also be an effective therapeutic strategy to eradicate doxorubicin resistant ER+MC.
Highlights
Despite the advances in mammary carcinoma (MC) treatment, the use of conventional chemotherapies, those containing anthracyclines, remains important in the treatment of all MC subtypes [1] neo-adjuvant chemotherapy remains the standard care for patients with locally advanced MC [2], where the use of an anthracycline containing regimen achieved a pathological complete response of 17.1% [3].As an adjuvant therapy, the use of anthracycline containing regimens significantly improved the 10-year recurrence free survival by 8% as well as produced a 5% reduction in MC mortality [4].Doxorubicin is one of the most widely used anthracyclines for the treatment of MC [5]
It is limited by the acquired doxorubicin resistance that can be driven by various mechanisms including the upregulation of efflux transporters, enhanced DNA damage repair as well as the suppression of downstream apoptotic signaling [11]
We showed that Trefoil Factor 3 (TFF3) reduces sensitivity and promotes acquired resistance to doxorubicin in estrogen receptor positive (ER+)MC
Summary
Despite the advances in MC treatment, the use of conventional chemotherapies, those containing anthracyclines, remains important in the treatment of all MC subtypes [1] neo-adjuvant chemotherapy remains the standard care for patients with locally advanced MC [2], where the use of an anthracycline containing regimen achieved a pathological complete response of 17.1% [3].As an adjuvant therapy, the use of anthracycline containing regimens significantly improved the 10-year recurrence free survival by 8% as well as produced a 5% reduction in MC mortality [4].Doxorubicin is one of the most widely used anthracyclines for the treatment of MC [5]. The use of anthracycline containing regimens significantly improved the 10-year recurrence free survival by 8% as well as produced a 5% reduction in MC mortality [4]. The effective use of doxorubicin is limited by its dose-dependent cardiotoxicity and evidence of doxorubicin-related congestive heart failure have been reported in doxorubicin treated patients [6,7,8,9,10] It is limited by the acquired doxorubicin resistance that can be driven by various mechanisms including the upregulation of efflux transporters, enhanced DNA damage repair as well as the suppression of downstream apoptotic signaling [11]. The development of potential combinatorial approaches to enhance the efficacy of doxorubicin without incurring further toxicity, and to overcome acquired doxorubicin resistance, is warranted
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