Abstract
Simple SummaryTumor hypoxia is known to increase the resistance of cancer cells to chemotherapy. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lack of target. Therefore, chemotherapy is the only approved systemic treatment in TNBC. Here, we synthesized the calcium peroxide-modified magnetic nanoparticles (CaO2-MNPs) with the function of oxygen generation to improve and enhance the therapeutic efficiency of doxorubicin treatment in the hypoxia microenvironment of TNBC. CaO2-MNPs promoted ubiquitination and protein degradation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, CaO2-MNPs inhibited autophagy and induced apoptosis in TNBC cells. CaO2-MNPs in combination with doxorubicin showed a stronger tumor-suppressive effect on TNBC compared to the doxorubicin treatment alone in an orthotopic mouse model. Our findings suggest that combined with CaO2-MNPs and doxorubicin attenuates HIF-1α expression to improve the efficiency of chemotherapy in TNBC.Cancer response to chemotherapy is regulated not only by intrinsic sensitivity of cancer cells but also by tumor microenvironment. Tumor hypoxia, a condition of low oxygen level in solid tumors, is known to increase the resistance of cancer cells to chemotherapy. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Due to lack of target in TNBC, chemotherapy is the only approved systemic treatment. We evaluated the effect of hypoxia on chemotherapy resistance in TNBC in a series of in vitro and in vivo experiments. Furthermore, we synthesized the calcium peroxide-modified magnetic nanoparticles (CaO2-MNPs) with the function of oxygen generation to improve and enhance the therapeutic efficiency of doxorubicin treatment in the hypoxia microenvironment of TNBC. The results of gene set enrichment analysis (GSEA) software showed that the hypoxia and autophagy gene sets are significantly enriched in TNBC patients. We found that the chemical hypoxia stabilized the expression of hypoxia-inducible factor 1α (HIF-1α) protein and increased doxorubicin resistance in TNBC cells. Moreover, hypoxia inhibited the induction of apoptosis and autophagy by doxorubicin. In addition, CaO2-MNPs promoted ubiquitination and protein degradation of HIF-1α. Furthermore, CaO2-MNPs inhibited autophagy and induced apoptosis in TNBC cells. Our animal studies with an orthotopic mouse model showed that CaO2-MNPs in combination with doxorubicin exhibited a stronger tumor-suppressive effect on TNBC, compared to the doxorubicin treatment alone. Our findings suggest that combined with CaO2-MNPs and doxorubicin attenuates HIF-1α expression to improve the efficiency of chemotherapy in TNBC.
Highlights
Triple-negative breast cancer (TNBC) is a subtype of breast cancer defined by the absence of progesterone receptor, estrogen receptor and human epidermal growth factor receptor 2 [1,2]
We showed the evidence that chemical hypoxia (CoCl2 ) stabilized hypoxia-inducible factor 1α (HIF-1α) protein (Figure 2A) and reduced cell death induced by doxorubicin in 4T1 cells (Figure 2B)
The hypoxia and autophagy gene sets were significantly enriched in TNBC patients, suggesting hypoxia and autophagy play a critical role in TNBC
Summary
Triple-negative breast cancer (TNBC) is a subtype of breast cancer defined by the absence of progesterone receptor, estrogen receptor and human epidermal growth factor receptor 2 [1,2]. Lack of expression of these proteins makes TNBC an orphan disease when considering standard therapeutic regimens for breast cancer [4]. Current treatments of TNBC often includes surgery, radiotherapy and chemotherapy. Due to lack of target in TNBC, chemotherapy is the only approved systemic treatment [1]. Previous studies have demonstrated that tumor hypoxia, a condition of low oxygen level in solid tumors, increases the resistance of cancer cells to chemotherapy and radiotherapy [5,6]. Hypoxia affected breast cancer cell growth dynamics, angiogenesis, migration, endoplasmic reticulum (ER) stress and aggressive features [7,8].
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