雷帕霉素降低老年乳腺干细胞癌变潜能的作用机制

Aging is the number one risk factor for breast cancer and more recent findings indicate that mammary stem cells may serve as the cellular origin of breast cancers. We for the first time reported that mammary stem cells derived from aged mice are prone to tumorigenesis. Rapamycin is the only known drug that has been shown to extend lifespan in mammals. Our earlier studies revealed that aged mammary stem cells and stromal cells (stem cell niche) are characterized with elevated immune and inflammatory signals. More recently, we found out that rapamycin can repress the tumorigenic potential of aged mammary stem cells and decrease the expression levels of inflammatory signals. Based on these findings, we hypothesize that rapamycin’s repressive role on tumorigenic potential of aged mammary stem cells is mediated by the inflammatory signaling pathway. To test this hypothesis, we will use the 18-month old FVB-GFP transgenic mouse as the model species and first optimize the rapamycin treatment dose and duration for the best inhibitory effect of tumorigenic potential of aged mammary stem cells. We will then profile transcriptional changes and secreted cytokines by RNAseq and cytokine panel analysis to identify gene/cytokine signatures that are specific and targeted by rapamycin. Finally, we will utilize various gene editing techniques as well as addition of agonist or antagonist to uncover the underlying molecular mechanism responsible for rapamycin’s repressive effect on tumorigenetic potential of aged mammary stem cells. Our findings will provide the foundation for future anti-inflammatory drug discovery for therapeutic breast cancer prevention and intervention in the high risk elderly women.

衰老是乳腺癌发生的高危因素，最新研究表明乳腺癌的原发细胞极有可能是乳腺干细胞。本课题组首次报道了衰老乳腺干细胞具有癌变的潜能。雷帕霉素是至今为止唯一被证实可延缓哺乳类衰老的药物。基于我们的前期研究结果衰老乳腺干细胞及其环境基质细胞发生变化最为显著的信号通路是炎症反应，以及有关雷帕霉素可显著减缓老龄小鼠乳腺干细胞癌变和降低炎症因子表达水平的最新发现，我们提出雷帕霉素对衰老乳腺干细胞癌变潜能的抑制作用是由炎症反应信号通路所介导的科学假说。本课题拟选取18月龄绿色荧光蛋白标记的转基因FVB小鼠为模型，首先筛选出雷帕霉素降低衰老乳腺干细胞癌变潜能的最佳处理时间和剂量，然后利用深度测序和炎症因子检测，查明雷帕霉素作用的特征基因和炎症因子，最后通过基因和炎症因子的调控来明确雷帕霉素降低衰老乳腺干细胞癌变潜能的分子机制。本研究结果将为今后开发抗炎药物来实现对老龄人群乳腺癌的预防和干预提供重要的科学依据。

衰老是乳腺癌发生的高危因素，最新研究表明乳腺癌的原发细胞极有可能是乳腺干细胞，衰老乳腺干细胞具有癌变的潜能，而雷帕霉素是至今为止唯一被证实可延缓哺乳类衰老的药物。基于我们的前期研究结果衰老乳腺干细胞及其环境基质细胞发生变化最为显著的信号通路是炎症反应，以及有关雷帕霉素可显著减缓老龄小鼠乳腺干细胞癌变和降低炎症因子表达水平的最新发现，我们提出雷帕霉素对衰老乳腺干细胞癌变潜能的抑制作用是由炎症反应信号通路所介导的科学假说。本课题选取18月龄绿色荧光蛋白标记的转基因FVB小鼠为模型，首先筛选出雷帕霉素降低衰老乳腺干细胞癌变潜能的最佳处理时间和剂量，然后利用深度测序和炎症因子检测，查明雷帕霉素作用的特征基因和炎症因子，最后通过基因和炎症因子的调控来明确雷帕霉素降低衰老乳腺干细胞癌变潜能的分子机制。研究发现，雷帕霉素对伴随衰老过程而出现的乳腺导管结构的异常变化具有显著的减缓作用，长期处理和短期处理均可以显著提高小鼠乳腺祖细胞/干细胞比例，降低干细胞频率，提高腔祖细胞频率而表现出更接近于年轻小鼠乳腺的特征，改善老龄小鼠乳腺干细胞的体外传代能力和体内移植再生能力，最终使老龄小鼠乳腺表现出近似年轻小鼠乳腺的状态。这可能是因为雷帕霉素通过mTOR信号通路调控炎症反应来恢复衰老干细胞功能。此外，D-半乳糖诱导的衰老模型也可导致小鼠乳腺炎症反应增强，改变了乳腺干细胞的体外自我更新能力、改变乳腺干细胞再生功能并增加再生乳腺的病理性增生。综上所述，本项目的研究结果揭示了雷帕霉素降低衰老乳腺干细胞癌变潜能的分子机制，为今后开发抗炎药物来实现对老龄人群乳腺癌的预防和干预提供重要的科学依据。