Please use this identifier to cite or link to this item: https://doi.org/10.3390/cancers11101528
Title: Inhibition of TFF3 enhances sensitivity—and overcomes acquired resistance—to doxorubicin in estrogen receptor-positive mammary carcinoma
Authors: Poh, H.M.
Chiou, Y.S.
Chong, Q.Y. 
Chen, R.-M. 
Rangappa, K.S.
Ma, L.
Zhu, T.
Kumar, A.P. 
Pandey, V.
Basappa
Lee, S.-C. 
Lobie, P.E. 
Keywords: Acquired resistance
Apoptosis
Dose-dependent toxicity
Doxorubicin
Mammary carcinoma
PI3K/AKT
Trefoil factor 3 (TFF3)
Issue Date: 2019
Publisher: MDPI AG
Citation: Poh, H.M., Chiou, Y.S., Chong, Q.Y., Chen, R.-M., Rangappa, K.S., Ma, L., Zhu, T., Kumar, A.P., Pandey, V., Basappa, Lee, S.-C., Lobie, P.E. (2019). Inhibition of TFF3 enhances sensitivity—and overcomes acquired resistance—to doxorubicin in estrogen receptor-positive mammary carcinoma. Cancers 11 (10) : 1528. ScholarBank@NUS Repository. https://doi.org/10.3390/cancers11101528
Rights: Attribution 4.0 International
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. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Source Title: Cancers
URI: https://scholarbank.nus.edu.sg/handle/10635/209544
ISSN: 2072-6694
DOI: 10.3390/cancers11101528
Rights: Attribution 4.0 International
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