The TGFα-EGFR-Akt signaling axis plays a role in enhancing proinflammatory chemokines in triple-negative breast cancer cells.
The TGFα-EGFR-Akt signaling axis plays a role in enhancing proinflammatory chemokines in triple-negative breast cancer cells.
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DOI：
10.18632/oncotarget.25389
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发表时间：
2018-06-29
期刊：
影响因子：
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通讯作者：
Son DS
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作者：
Ignacio RMC;Gibbs CR;Lee ES;Son DS
三阴性乳腺癌（TNBC）具有侵袭性，通常预后较差。趋化因子具有肿瘤转移的趋化潜能。在这里，我们研究了BC亚型的趋化因子特征以及TNBC中增强促炎趋化因子的潜在机制。来自微阵列数据集的分析显示，与非TNBC相比，包括TNBC在内的基底样BC亚型主要表达促炎趋化因子，如CXCL1和8。趋化因子PCR阵列证实了TNBC细胞中的显性趋化因子。为了确定TNBC细胞中促炎趋化因子的驱动因子，我们测定了表皮生长因子受体（EGFR）家族成员的表达和信号谱。与非TNBC细胞相比，TNBC细胞表达更高水平的EGFR和磷酸化Akt/Erk。此外，EGF进一步增强了TNBC细胞中的促炎趋化因子，包括CXCL2。Akt的下调降低了CXCL2启动子的活性，而Akt的过表达则增强了其活性。Akt抑制剂MK2206降低CXCL2启动子活性，而抑制和敲低Erk不降低其活性。我们发现转化生长因子α (TGFα)可以作为EGFR的主要配体，在TNBC细胞中驱动EGFR介导的Akt活化。MK2206降低TGFα启动子活性，而过表达Akt则使其升高。MK2206也能减少TNBC细胞的tgf - α释放。此外，MK2206下调CXCL2 mRNA表达，而TGFα上调CXCL2 mRNA表达。综上所述，tgf - α- egfr - akt信号轴可以在TNBC中增强促炎趋化因子的表达，随后促进炎症负担，最终导致TNBC患者的癌症进展和更高的死亡率。
Triple-negative breast cancer (TNBC) is aggressive and typically has a poor prognosis. Chemokines have chemoattractant potential for cancer metastasis. Here, we investigated the chemokine signatures in BC subtypes and the underlying mechanisms that enhance proinflammatory chemokines in TNBC. Analysis from microarray dataset revealed that basal-like BC subtype including TNBC expressed dominantly proinflammatory chemokines, such as CXCL1 and 8, compared to non-TNBC. Chemokine PCR array confirmed the dominant chemokines in TNBC cells. To identify a driving factor for proinflammatory chemokines in TNBC cells, we determined the expression and signaling profiles of epidermal growth factor receptor (EGFR) family members. TNBC cells expressed higher levels of EGFR and phosphorylated Akt/Erk than non-TNBC cells. In addition, EGF further enhanced the proinflammatory chemokines in TNBC cells, including CXCL2. Knockdown of Akt reduced the CXCL2 promoter activity, while overexpression of Akt enhanced it. MK2206, an Akt inhibitor, reduced the CXCL2 promoter activity, while inhibition and knockdown of Erk did not reduce its activity. We found that transforming growth factor alpha (TGFα) could serve as a main ligand for EGFR to drive EGFR-mediated Akt activation in TNBC cells. MK2206 decreased TGFα promoter activity, while overexpression of Akt increased it. MK2206 also reduced TGFα release from TNBC cells. Moreover, MK2206 downregulated CXCL2 mRNA expression, while TGFα upregulated it. Taken together, the TGFα-EGFR-Akt signaling axis can play a role in enhancing proinflammatory chemokine expression in TNBC, subsequently contributing to the inflammatory burden that ultimately lead to cancer progression and a higher mortality rate among TNBC patients.