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

Monica K VanKlompenberg; Emily Leyden; Anne H Arnason; Jian-Ting Zhang; Casey D Stefanski; Jenifer R Prosperi

doi:10.18632/oncotarget.22263

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

Oncotarget. 2017 Nov 1;8(61):102868-102879. doi: 10.18632/oncotarget.22263. eCollection 2017 Nov 28.

Authors

Monica K VanKlompenberg^{1

2

3}, Emily Leyden^{2

4}, Anne H Arnason^{2

4}, Jian-Ting Zhang⁵, Casey D Stefanski^{2

4}, Jenifer R Prosperi^{1

2

4}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA.
² Harper Cancer Research Institute, South Bend, IN, USA.
³ Current address: Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
⁴ Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
⁵ Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.

Abstract

Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT;Apc^Min/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT;Apc^Min/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT;Apc^Min/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.

Keywords: Adenomatous Polyposis Coli; STAT3; breast cancer; chemoresistance; doxorubicin.

Grants and funding

UL1 TR001108/TR/NCATS NIH HHS/United States