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APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells.

ABSTRACT: Chemoresistance is one of the leading causes of cancer-related deaths in the United States. Triple negative breast cancer (TNBC), a subtype lacking the known breast cancer receptors used for targeted therapy, is reliant on chemotherapy as the standard of care. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 70% of sporadic breast cancers with APC-deficient tumors resembling the TNBC subtype. Using mammary tumor cells from the ApcMin/+ mouse model crossed to the Polyoma middle T antigen (PyMT) transgenic model, we previously showed that APC loss decreased sensitivity to doxorubicin (DOX). Understanding the molecular basis for chemoresistance is essential for the advancement of novel therapeutic approaches to ultimately improve patient outcomes. Resistance can be caused via different methods, but here we focus on the DNA repair response with DOX treatment. We show that MMTV-PyMT;ApcMin/+ cells have decreased DNA damage following 24 hour DOX treatment compared to MMTV-PyMT;Apc+/+ cells. This decreased damage is first observed 24 hours post-treatment and continues throughout 24 hours of drug recovery. Activation of DNA damage response pathways (ATM, Chk1, and Chk2) are decreased at 24 hours DOX-treatment in MMTV-PyMT;ApcMin/+ cells compared to control cells, but show activation at earlier time points. Using inhibitors that target DNA damage repair kinases (ATM, ATR, and DNA-PK), we showed that ATM and DNA-PK inhibition increased DOX-induced apoptosis in the MMTV-PyMT;ApcMin/+ cells. In the current work, we demonstrated that APC loss imparts resistance through decreased DNA damage response, which can be attenuated through DNA repair inhibition, suggesting the potential clinical use of DNA repair inhibitions as combination therapy.

SUBMITTER: Stefanski CD

PROVIDER: S-EPMC6872841 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells.

Stefanski Casey D CD Keffler Kaitlyn K McClintock Stephanie S Milac Lauren L Prosperi Jenifer R JR

Neoplasia (New York, N.Y.) 20191120 12

Chemoresistance is one of the leading causes of cancer-related deaths in the United States. Triple negative breast cancer (TNBC), a subtype lacking the known breast cancer receptors used for targeted therapy, is reliant on chemotherapy as the standard of care. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 70% of sporadic breast cancers with APC-deficient tumors resembling the TNBC subtype. Using mammary tumor cells from the Apc<sup>Min/+</sup> mouse model ...[more]

PMID: 31759252

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Project description:BackgroundThe pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport. This function is likely to be activated under conditions of stress. A number of studies support the notion that CC3 acts as a tumor and metastasis suppressor in various types of cancer. The yeast homolog of CC3 is likely to be involved in responses to DNA damage. Here we examined the potential role of CC3 in regulation of cellular responses to genotoxic stress.ResultsWe found that forced expression of CC3 in CC3-negative cells strongly delays the repair of UV-induced DNA damage. Exogenously introduced CC3 negatively affects expression levels of DDB2/XPE and p21CIP1, and inhibits induction of c-FOS after UV exposure. In addition, exogenous CC3 prevents the nuclear accumulation of P21CIP in response to UV. These changes in the levels/localization of relevant proteins resulting from the enforced expression of CC3 are likely to contribute to the observed delay in DNA damage repair. Silencing of CC3 in CC3-positive cells has a modest delaying effect on repair of the UV induced damage, but has a much more significant negative affect on the translesion DNA synthesis after UV exposure. This could be related to the higher expression levels and increased nuclear localization of p21CIP1 in cells where expression of CC3 is silenced. Expression of CC3 also inhibits repair of oxidative DNA damage and leads to a decrease in levels of nucleoredoxin, that could contribute to the reduced viability of CC3 expressing cells after oxidative insult.ConclusionsManipulation of the cellular levels of CC3 alters expression levels and/or subcellular localization of proteins that exhibit nucleocytoplasmic shuttling. This results in altered responses to genotoxic stress and adversely affects DNA damage repair by affecting the recruitment of adequate amounts of required proteins to proper cellular compartments. Excess of cellular CC3 has a significant negative effect on DNA repair after UV and oxidant exposure, while silencing of endogenous CC3 slightly delays repair of UV-induced damage.

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APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells.

Publications

APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells.

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