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APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation

Monica K VanKlompenberg1,2,3, Emily Leyden2,4, Anne H Arnason2,4

  • 1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA.

Oncotarget
|December 22, 2017
PubMed

Insights

Loss of Adenomatous Polyposis Coli (APC) causes breast cancer chemotherapeutic resistance by increasing STAT3 activation. Inhibiting STAT3 restores drug sensitivity and reduces tumor-initiating cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Chemotherapy resistance is a major cause of breast cancer mortality.
  • Loss of Adenomatous Polyposis Coli (APC) in MMTV-PyMT mice confers resistance to cisplatin and doxorubicin.
  • Understanding the mechanisms of APC-mediated resistance is crucial for improving treatment outcomes.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying APC-mediated chemotherapeutic resistance in breast cancer.
  • To investigate the role of Signal Transducer and Activator of Transcription 3 (STAT3) in this resistance.
  • To explore potential therapeutic strategies targeting STAT3.

Main Methods:

  • Utilized the MMTV-PyMT;Apc^-/- mouse model.
  • Assessed STAT3 activation and its downstream targets, including Multidrug Resistance Protein 1 (MDR1).
  • Investigated the role of Epidermal Growth Factor Receptor (EGFR) in STAT3 activation.
  • Administered STAT3 inhibitor A69 in combination with chemotherapeutic agents.

Main Results:

  • Loss of APC in MMTV-PyMT mice led to increased STAT3 activation, independent of IL-6.
  • Enhanced EGFR expression was implicated in elevated STAT3 activation.
  • STAT3 inhibition (A69) combined with doxorubicin restored drug sensitivity and decreased MDR1 expression and tumor-initiating cells.
  • STAT3 inhibition did not restore sensitivity to cisplatin.

Conclusions:

  • Loss of APC promotes breast cancer chemotherapeutic resistance through enhanced STAT3 activation.
  • STAT3 signaling, potentially driven by EGFR, plays a key role in maintaining drug resistance and tumor-initiating cells.
  • Targeting STAT3 offers a promising strategy to overcome doxorubicin resistance in APC-deficient breast cancers.
Keywords:
Adenomatous Polyposis ColiSTAT3breast cancerchemoresistancedoxorubicin

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