Inhibition of TFF3 enhances sensitivity—and overcomes acquired resistance—to doxorubicin in estrogen receptor-positive mammary carcinoma

Han Ming Poh, Yi Shiou Chiou, Qing Yun Chong, Ru Mei Chen, Kanchugarakoppal S. Rangappa, Lan Ma, Tao Zhu, Alan Prem Kumar, Vijay Pandey, Basappa, Soo Chin Lee, Peter E. Lobie

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Article number1528
JournalCancers
Volume11
Issue number10
DOIs
StatePublished - Oct 2019

Keywords

  • Acquired resistance
  • Apoptosis
  • Dose-dependent toxicity
  • Doxorubicin
  • Mammary carcinoma
  • PI3K/AKT
  • Trefoil factor 3 (TFF3)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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