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Prosperi Lab
APC and chemotherapy resistance in breast cancer
The Adenomatous Polyposis Coli (APC) tumor suppressor is either mutated or hypermethylated in up to 70% of sporadic breast cancer.
Work done by a former post-doc demonstrated APC loss decreases apoptosis induced by paclitaxel, cisplatin, or doxorubicin (VanKlompenberg, et al, 2015). Below, you will find information about the impact of APC loss on each of these 3 drugs.
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If you are interested in joining this exciting project, please email us!
Doxorubicin
APC-mutant cells have increased Signal Transducer and Activator of Transcription 3 (STAT3) expression. Combination therapy with A69, a STAT3 inhibitor, restored doxorubicin sensitivity; however, STAT3 inhibition had no effect on cisplatin sensitivity.
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In breast cancer, the tumor initiating cell (TIC) population has been shown to be maintained via constitutively active STAT3. APC-mutant cells have an increased TIC population. STAT3 also upregulates multidrug resistance protein 1 (MDR1), a known doxorubicin efflux pump. APC-mutant cells have an increased MDR1 expression. We hypothesize that APC loss regulates doxorubicin resistance via STAT3-induced MDR1 expression and enhanced TIC population.
Paclitaxel
We have shown that APC-mutant cells are resistant to treatment with Paclitaxel (VanKlompenberg et al, 2015). We have performed an unbiased gene expression assay to uncover new pathways that are responsible for the resistant phenotype. Current studies are investigating cell cycle control and signaling pathways identified in the array.
Cisplatin
We observed enhanced proliferation downstream of APC mutations through focal adhesion kinase (FAK)/Src/JNK signaling (Prosperi et al, 2011). Using Src (PP2) or JNK (SP600125) inhibitors, cisplatin-induced apoptosis was restored in APC-mutant cells (VanKlompenberg et al, 2015).
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Current studies are investigating how APC loss induces cisplatin resistance through increased detoxification and/or increased DNA repair mechanisms.