Abstract
BackgroundTriple-negative breast cancer (TNBC) is the most intractable type of breast cancer, and there is a lack of effective targeted therapy. Insulin-like growth factor-1 receptor (IGF-1R) is reportedly a potential target for TNBC treatment. However, satisfying treatment outcomes in breast cancer patients have yet to be achieved with IGF-1R-targeted agents.MethodsTo confirm whether inhibiting IGF-1R could induce autophagy, we detected autophagy-related proteins by western blotting and immunofluorescence staining of LC3-II. The IGF-1R inhibitor NVP-AEW541, autophagy inhibitor 3-methyladenine (3-MA) and Atg7 small interfering RNA (siRNA) were used to further investigate the effects of autophagy induced by IGF-1R inhibition in TNBC cells. The CCK8 assay, EdU assay, apoptosis and cell cycle analyses were applied to test cell function after treatment.ResultsNVP-AEW541 markedly induced autophagy in TNBC cells by increasing the levels of the autophagy-related protein Beclin-1 and the LC3-II/LC-I ratio and reducing the selective autophagy substrate p62. Joint application of 3-MA or Atg7 siRNA enhanced the cell growth inhibition and apoptosis effects of NVP-AEW541 by arresting cells at G1/G0 phase and increasing Bax expression and decreasing that of Bcl-2.ConclusionTargeting IGF-1R in TNBC induces cell-protective autophagy, thereby weakening the therapeutic effect of agents directed toward IGF-1R. Our findings reveal that combined use autophagy-disrupting agents can enhance the therapeutic efficacy of IGF-1R inhibitors in TNBC cells and may provide a valuable treatment strategy for IGF-1R inhibitor-based therapies for TNBC and other IGF-1 signaling-associated tumors.
Highlights
Breast cancer is the second most prevalent cancer worldwide and according to an investigation by the World Health Organization, represents one of the leading causes of death in women cancer patients [1, 2].Breast cancer can be divided into five major subtypes: luminal A, luminal B, Her-2-overexpressing, normal breast-like and basal-like subtypes
Our findings reveal that combined use autophagy-disrupting agents can enhance the therapeutic efficacy of Insulin-like growth factor-1 receptor (IGF-1R) inhibitors in Triple-negative breast cancer (TNBC) cells and may provide a valuable treatment strategy for IGF-1R inhibitor-based therapies for TNBC and other Insulin-like growth factor-1 (IGF-1) signaling-associated tumors
To investigate the effect of IGF-1R on TNBC cells, we chose a selective inhibitor of IGF-1R, NVP-AEW541[21], to down-regulate the level of phosphorylated IGF-1R in MDA-MB-231 and BT-549 cells
Summary
Breast cancer is the second most prevalent cancer worldwide and according to an investigation by the World Health Organization, represents one of the leading causes of death in women cancer patients [1, 2].Breast cancer can be divided into five major subtypes: luminal A, luminal B, Her-2-overexpressing, normal breast-like and basal-like subtypes. The majority of basal-like subtype tumors are triple-negative breast cancer (TNBC), which are highly malignant tumors. In this case, ‘triple negative’ indicates that no expression of estrogen-receptor (ER), progesterone-receptor (PR), and human epidermal growth factor receptor 2 (HER-2) is found in this type of breast cancer [3]. TNBC accounts for approximately 15% to 20% of all breast cancer cases and is usually associated with a relatively poor prognosis due to its aggressive behavior and the lack of effective targeting therapies compared with other subtypes [3]. Triple-negative breast cancer (TNBC) is the most intractable type of breast cancer, and there is a lack of effective targeted therapy. Satisfying treatment outcomes in breast cancer patients have yet to be achieved with IGF-1R-targeted agents
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