乳腺癌微环境中癌相关成纤维细胞分泌IL-6介导三苯氧胺耐药的研究

Breast cancer is one of the major malignant tumors which threaten women's lives and health. ER positive breast cancer can receive endocrine therapy, like tamoxifen (TAM), but there still exists treatment resistance. Tumor microenvironment status alternation is associated with TAM resistance, whose fibroblasts can be activated into breast cancer-associated fibroblasts (CAF), increasing IL-6 secretion, and also induce epithelial mesenchymal transition (EMT) process occurrence in breast cancer. IL-6 can activate EMT associated PI3K/Akt/mTOR signaling pathway, leading to EMT process occurrence in breast cancer, which can be related with TAM treatment resistance. Our previous study demonstrated that PI3K/Akt/mTOR signaling pathway inhibitors can reverse IL-6 mediated EMT process in breast cancer and significantly enhance TAM treatment sensitivity in vitro. In this present study, we intend to analyze the influence of tumor microenvironment CAF secreating IL-6 on breast cancer biological behaviors, signaling pathway status, EMT status as well as TAM treatment sensitivity, and to assess and validate whether targeting IL-6 and PI3K/Akt/mTOR signaling pathway can reverse TAM resistance and to find out its potential anti-tumor mechanism, so as to further improve breast cancer endocrine therapy efficacy.

乳腺癌是威胁女性生命健康的主要恶性肿瘤之一,ER阳性乳腺癌可接受三苯氧胺（TAM）等内分泌治疗，但存在耐药。TAM耐药可能与肿瘤微环境的改变相关，肿瘤间质中的成纤维细胞可被激活成为乳腺癌相关成纤维细胞（CAF），引起IL-6分泌的增加，并可促进乳腺癌细胞发生上皮间质转化（EMT）。IL-6可激活EMT相关的PI3K/Akt/mTOR信号通路，介导乳腺癌细胞EMT的发生，引起TAM治疗的耐药。我们早期研究提示PI3K/Akt/mTOR信号通路抑制剂可逆转IL-6引起的EMT发生，并在体外试验中显著提高乳腺癌TAM治疗的敏感性。在本研究中，我们拟分析乳腺癌微环境中的CAF分泌IL-6对乳腺癌细胞生物学行为、信号通路状态、EMT状态以及TAM治疗敏感性的影响，评估并验证靶向作用IL-6和PI3K/Akt/mTOR信号通路对TAM耐药的逆转作用和潜在作用机制，从而进一步提高乳腺癌内分泌治疗的疗效。

乳腺癌是威胁女性生命健康的主要恶性肿瘤之一,ER阳性乳腺癌可接受三苯氧胺（TAM）等内分泌治疗，但存在耐药。TAM 耐药可能与肿瘤微环境的改变相关,但具体机制目前尚不明确。我们的研究发现肿瘤间质中的成纤维细胞可被激活成为乳腺癌相关成纤维细胞（CAF），且CAF能够降低ER阳性乳腺癌细胞系对TAM的敏感性。进一步研究发现，CAF能够增加 IL-6 的分泌，并可促进乳腺癌细胞发生上皮间质转化（EMT）；同时，IL-6 可激活 EMT 相关的 PI3K/Akt/mTOR和JAK/STAT3 信号通路，介导乳腺癌细胞 EMT 的发生，进而引起 TAM 治疗的耐药。我们利用IL-6 中和抗体、STAT3抑制剂及 PI3K/Akt/mTOR 信号通路抑制剂BKM120、BEZ235实现对CAF诱导 TAM 耐药的逆转，并发现上述药物可以抑制PI3K/Akt/mTOR和JAK/STAT3 信号通路，并逆转EMT。同时，我们在小鼠体内进一步验证上述结果，发现将CAF中IL-6基因敲除之后，肿瘤对三苯氧胺治疗敏感性恢复，且可逆转EMT。本研究成功探索CAF诱导三苯氧胺治疗耐药的作用机制，即通过分泌IL-6，激活EMT相关的PI3K/Akt/mTOR和JAK/STAT3 信号通路，介导ER+乳腺癌细胞 EMT 的发生，最终引起 TAM 治疗的耐药；同时我们也验证靶向IL-6和PI3K/Akt/mTOR、JAK/STAT3信号通路及敲除IL-6基因对 TAM 耐药的逆转作用，为进一步提高乳腺癌内分泌治疗的疗效提供理论基础，具有重要的转化医学意义。