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.