Abstract
Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and multiple TAM-secreted cytokines have been identified associating with poor clinical outcomes. However, the therapeutic targets existing in the loop between TAMs and cancer cells are still required for further investigation. Here in, cytokine array validated that C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant chemokine secreted by TAMs, and CXCL1 can promote breast cancer migration and invasion ability, as well as epithelial–mesenchymal transition in both mouse and human breast cancer cells. QPCR screening further validated SOX4 as the highest responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 binds to SOX4 promoter and activates its transcription via NF-κB pathway. In vivo breast cancer xenografts demonstrated that CXCL1 silencing in TAMs results in a significant reduction in breast cancer growth and metastatic burden. Bioinformatic analysis and clinical investigation finally suggested that high CXCL1 expression is significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Taken together, our results indicated that TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/SOX4 activation, and CXCL1-based therapy might become a novel strategy for breast cancer metastasis prevention.
Highlights
Breast cancer is the most frequent cancer among women and the second most common cause of cancer deaths worldwide, with an estimated 1.67 million new cases and 521,900 premature deaths in 20121
CXCL1 was significantly elevated in the metastatic lesions, accompanied by the increased expression of arginase 1 (Arg-1) and epithelial–mesenchymal transition (EMT)-related markers including β-catenin, vimentin and N-cadherin
The results showed that CXCL1-induced sex determining region Y-box 4 (SOX4) overexpression was blocked by Bay 11–7082 treatment, accompanied by the increased expression of E-cadherin and reduction of vimentin and β-catenin (Fig. 5c), suggesting that the NF-κB pathway is critical in mediating CXCL1-induced metastasis
Summary
Breast cancer is the most frequent cancer among women and the second most common cause of cancer deaths worldwide, with an estimated 1.67 million new cases and 521,900 premature deaths in 20121. Advances have been made in novel drug discovery and Macrophages are the most abundant stromal cells associated with the host immune system in multiple malignancies. Wang et al Cell Death and Disease (2018)9:880 onset, and progression, and exist as classically activated macrophages (M1) and alternatively activated macrophages (M2 or tumor-associated macrophages, TAMs)[4]. The density of TAMs was found to correlate with a poor prognosis in multiple malignancies, including breast cancer[5]. The macrophage-stimulating protein pathway promotes breast cancer metastasis and predicts a poor prognosis[8]. Targeting stromal TAMs may be promising for preventing cancer development and metastasis
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