Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

中文翻译：

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细胞外S100A8 / A9触发的MCAM-ETV4轴在乳腺癌侵袭性中的关键作用。

转移性乳腺癌是女性癌症相关死亡的主要原因。这种致命疾病的进展与促进癌细胞生长和扩散的炎症反应有关，最终导致总体存活率降低。但是，炎症促进癌症进展的机制仍然不清楚。在这项研究中，我们首次发现细胞外细胞因子S100A8 / A9在与细胞表面受体黑素瘤细胞粘附分子（MCAM）结合后会加速乳腺癌的生长和转移。我们的分子分析揭示了ETS易位变体4（ETV4）在体外和体内乳腺癌进展中的重要作用，该变体在S100A8 / A9刺激下在MCAM下游区域被显着激活。MCAM介导的ETV4激活在细胞中诱导了一种称为上皮-间充质转化（EMT）的移动表型，因为我们发现ETV4在很高的水平上转录上调ZEB1（一种强大的EMT诱导剂）。相反，MCAM或ETV4的下调会抑制EMT，导致肿瘤生长和肺转移大大减弱。总的来说，我们的结果表明ETV4是受S100A8 / A9-MCAM轴调控的新型转录因子，它通过ZEB1导致EMT，从而在乳腺癌细胞中转移。因此，基于我们的发现的治疗策略可能会改善患者的预后。MCAM或ETV4的下调抑制了EMT，导致肿瘤生长和肺转移大大减弱。总的来说，我们的结果表明ETV4是受S100A8 / A9-MCAM轴调控的新型转录因子，它通过ZEB1导致EMT，从而在乳腺癌细胞中转移。因此，基于我们的发现的治疗策略可能会改善患者的预后。MCAM或ETV4的下调抑制了EMT，导致肿瘤生长和肺转移大大减弱。总的来说，我们的结果表明ETV4是受S100A8 / A9-MCAM轴调控的新型转录因子，它通过ZEB1导致EMT，从而在乳腺癌细胞中转移。因此，基于我们的发现的治疗策略可能会改善患者的预后。