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 Prosperi

Research output: Contribution to journalArticle

2 Citations (Scopus)

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;ApcMin/+ 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;ApcMin/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT;ApcMin/+ 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.

Original languageEnglish (US)
Pages (from-to)102868-102879
Number of pages12
JournalOncotarget
Volume8
Issue number61
DOIs
StatePublished - Jan 1 2017

Fingerprint

STAT3 Transcription Factor
Adenomatous Polyposis Coli
Mouse mammary tumor virus
Doxorubicin
Transcriptional Activation
Breast Neoplasms
Neoplastic Stem Cells
P-Glycoprotein
Cisplatin
Transgenic Mice
Population
Cause of Death
Interleukin-6
Up-Regulation
Apoptosis
Gene Expression
Drug Therapy
Pharmaceutical Preparations

Keywords

  • Adenomatous Polyposis Coli
  • Breast cancer
  • Chemoresistance
  • Doxorubicin
  • STAT3

ASJC Scopus subject areas

  • Oncology

Cite this

VanKlompenberg, M. K., Leyden, E., Arnason, A. H., Zhang, J-T., Stefanski, C. D., & Prosperi, J. (2017). APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation. Oncotarget, 8(61), 102868-102879. https://doi.org/10.18632/oncotarget.22263

APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation. / VanKlompenberg, Monica K.; Leyden, Emily; Arnason, Anne H.; Zhang, Jian-Ting; Stefanski, Casey D.; Prosperi, Jenifer.

In: Oncotarget, Vol. 8, No. 61, 01.01.2017, p. 102868-102879.

Research output: Contribution to journalArticle

VanKlompenberg, MK, Leyden, E, Arnason, AH, Zhang, J-T, Stefanski, CD & Prosperi, J 2017, 'APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation', Oncotarget, vol. 8, no. 61, pp. 102868-102879. https://doi.org/10.18632/oncotarget.22263
VanKlompenberg MK, Leyden E, Arnason AH, Zhang J-T, Stefanski CD, Prosperi J. APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation. Oncotarget. 2017 Jan 1;8(61):102868-102879. https://doi.org/10.18632/oncotarget.22263
VanKlompenberg, Monica K. ; Leyden, Emily ; Arnason, Anne H. ; Zhang, Jian-Ting ; Stefanski, Casey D. ; Prosperi, Jenifer. / APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation. In: Oncotarget. 2017 ; Vol. 8, No. 61. pp. 102868-102879.
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