Abstract
In this study, GFP-tagged TNBC 4T1 cells with down-regulated TLR5 expression (TLR5− 4T1) and normal TLR5 expression (TLR5+ 4T1) were constructed, respectively. RT-PCR and Western blot studies showed that down-regulation of TLR5 obviously increased the expression of VEGFR in 4T1 cells. Highly stable radio-probes 125I-anti-TLR5 mAb/125I-VEGF/125I-IgG were obtained with labeling rates over 85% and radiochemical purities above 90%. Among these three probes, 125I−anti−TLR5 mAb and 125I-VEGF were used for specifically imaging TNBC, while 125I-IgG was used for comparison. Whole-body phosphorus autoradiography showed clear imaging at 48 h after injection of 125I-anti-TLR5 mAb and 125I-VEGF also provided clear imaging at 24 h. Biodistribution study demonstrated a higher tumor uptake of 125I-anti-TLR5 mAb in TLR5+ group compared with that in TLR5− group (P < 0.05), whereas tumor uptake of 125I-VEGF in TLR5+ group was lower than that in the TLR5− group (P < 0.05). Immunohistochemical staining suggested that the expression of TLR5 was lower, whereas the expression of VEGFR, CD31, and MVD (microvessel density) was higher in TLR5− tumor-bearing mice. In summary, the down-regulation of TLR5 in TNBC promoted the VEGFR expression and angiogenesis, resulting in the proliferation of TNBC cells. TLR5/VEGF might be a better indicator for monitoring the development of TNBC.
Highlights
Breast cancer is the most common malignant tumor in women, and TNBC accounts for about 15% of breast cancer [1]
Compared with the 4T1 TLR5+ cells, the expression of TLR5 mRNA and protein was obviously decreased (P < 0.05), whereas the expression of VEGFR mRNA and protein was apparently increased in 4T1 TLR5− cells (P < 0.05, Figure 1), which indicated that TLR5 down-regulation apparently increased the expression of VEGFR in 4T1 cells
There was a negative correlation between TLR5 and VEGFR expression in 4T1 tumors (r2 = 0.7972; P < 0.01, Figure 6C). These results revealed that down-regulation of TLR5 in TNBC promoted VEGFR expression and angiogenesis, which may have participated in the tumor invasion and metastasis
Summary
Breast cancer is the most common malignant tumor in women, and TNBC accounts for about 15% of breast cancer [1]. Chemotherapy is still the only systemic therapy in clinics [3, 4], and the treatment effect is not ideal when it is in the advanced stage. It is of great significance and importance to TLR5 Increased VEGFR Expression in TNBC search for novel targets for early diagnosis of TNBC with high selectivity and to clarify the underlying mechanism. Angiogenesis is a promising target for TNBC, and vascular endothelial growth factor (VEGF) has been considered as an important angiogenic factor at present [5]. Angiogenesis inhibitors, such as bevacizumab and sorafenib, showed relative therapeutic effects for TNBC in clinics [11]
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