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.