APC Loss Prevents Doxorubicin-Induced Cell Death by Increasing Drug Efflux and a Chemoresistant Cell Population in Breast Cancer
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Published:2023-04-21
Issue:8
Volume:24
Page:7621
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Stefanski Casey D.12, Arnason Anne12ORCID, Maloney Sara23, Kotsen Janna12, Powers Elizabeth12ORCID, Zhang Jian-Ting4, Prosperi Jenifer R.123
Affiliation:
1. Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA 2. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA 3. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, IN 46617, USA 4. Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43606, USA
Abstract
Chemoresistance is a major health concern affecting cancer patients. Resistance is multifactorial, with one mechanism being the increased expression of ABC transporters (such as MDR1 and MRP1), which are drug efflux transporters capable of preventing intracellular accumulation of drugs and cell death. Our lab showed that the loss of Adenomatous Polyposis Coli (APC) caused an intrinsic resistance to doxorubicin (DOX), potentially through an enhanced tumor-initiating cell (TIC) population and the increased activation of STAT3 mediating the expression of MDR1 in the absence of WNT being activated. Here, in primary mouse mammary tumor cells, the loss of APC decreased the accumulation of DOX while increasing the protein levels of MDR1 and MRP1. We demonstrated decreased APC mRNA and protein levels in breast cancer patients compared with normal tissue. Using patient samples and a panel of human breast cancer cell lines, we found no significant trend between APC and either MDR1 or MRP1. Since the protein expression patterns did not show a correlation between the ABC transporters and the expression of APC, we evaluated the drug transporter activity. In mouse mammary tumor cells, the pharmacological inhibition or genetic silencing of MDR1 or MRP1, respectively, decreased the TIC population and increased DOX-induced apoptosis, supporting the use of ABC transporter inhibitors as therapeutic targets in APC-deficient tumors.
Funder
American Cancer Society’s Research Society Grant American Cancer Society’s Institutional Research Grant, the Navari Family Foundation Indiana CTSI an IITP fellowship from the Walther Cancer Foundation
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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