Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, which is very difficult to treat and commonly develops resistance to chemotherapy. The following study investigated whether the inhibition of Flap Endonuclease 1 (FEN1) expression, the key enzyme in the base excision repair (BER) pathway, could improve the anti-tumor effect of arsenic trioxide (ATO), which is a reactive oxygen species (ROS) inducer. Our data showed that ATO could increase the expression of FEN1, and the knockdown of FEN1 could significantly enhance the sensitivity of TNBC cells to ATO both in vitro and in vivo. Further mechanism studies revealed that silencing FEN1 in combination with low doses of ATO might increase intracellular ROS and reduce glutathione (GSH) levels, by reducing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2); elevating ROS leaded to apoptosis and p38 and JNK pathway activating. In conclusion, our study suggested the combination of FEN1 knockdown and ATO could induce TNBC cell death by promoting ROS production. FEN1 knockdown can effectively decrease the application concentrations of ATO, thus providing a possibility for the treatment of TNBC with ATO.
Highlights
Breast cancer is a disease with the highest morbidity in malignant tumors in women [1]
The results showed that arsenic trioxide (ATO) suppressed Triple-negative breast cancer (TNBC) cells growth in a time- and dose- dependent manner (Figure 1A)
Normal cells could maintain a lower reactive oxygen species (ROS) level than tumor cells and tolerate a certain degree of oxidative stress [29]. These tumor cells have more peroxiredoxins to protect from oxidative damage, suggesting that tumor cells are more reliant on the antioxidant system and more sensitive to exogenous oxidative stimuli
Summary
Breast cancer is a disease with the highest morbidity in malignant tumors in women [1]. Based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER 2) in tumor cells, breast cancer can be divided into multiple subtypes. TNBC, a subtype accounting for about 20% of all breast cancers [2, 3], tends to be more aggressive and difficult to treat. The women under the age of 40 years old with TNBC has poor clinical outcomes and disproportionately higher prevalence [4]. Chemotherapy is considered the main treatment approach for TNBC patients; followed by surgery and radiotherapy, the treatment effect is limited, and most patients occur disease progression in a relatively short time span [5].
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