阴虚气郁体质对乳腺癌发病的影响及其可能的分子机制

Breast cancer is the commonly occurring cancer severely threatening the life and health of women. It is very significant to deeply research the etiology of breast cancer through the lens of TCM constitutions and thus to find the effective prevention methods from Traditional Chinese Medicine approaches. Based on the deep thinking to the progress of some relevant studies and the preliminary results producted by our previous studies, our research team provide the hypotheses are: 1) Yin-deficiency and Qi-depression constitution might be the susceptible constitution types to breast cancer; 2) excessive activation of P13K/AKT/mTOR sigaling pathway, leading to the overexpression of PKM2, might be the major potential biological mechanisms of Yin-deficiency and Qi-stagnation constitution susceptible to breast cancer. The present study would like to utilize the research methods combined a clinical investigation with an animal experiment to confirm the hypotheses, which will be conducted simultaneously. An epidemiological survey with large samples will be used to investigate and compare the distribution patern of TCM constitution types among women with breast cancer and those without breast cancer, so as to objectively evaluate the effects of the constitution of Yin-deficiency and Qi-stagnation on the occurrence of breast cancer; The animal experiment, besides systematically examining the effects of Yin-deficiency and Qi-stagnation situation induced by long-term irritation on the acceleration of DMBA induing breast cancer rats model, will also observe the effects of this sutuation on the expression of mTOR sigaling pathway and PKM2 in those induced tumor tissues. The findings will not only determine whether TCM constitution of Yin-deficiency and Qi-stagnation is an independent risk factor to breast cancer, but also reveal the rationality that using the theories of TCM constitution to explain the etiology of breast cancer from macro-level and molecular level, which will greatly contribute to find corresponding TCM appoaches to prevent breast cancer in further studies.

乳腺癌是严重威胁妇女生命健康的常见恶性肿瘤，深入研究其中医体质发病学机理对寻求相应的中医药预防措施意义重大。本课题组在对前期研究数据及相关研究进展综合分析的基础上，提出"阴虚气郁质为乳腺癌的易发体质，阴虚气郁状态下mTOR通路的异常活化及PKM2的高表达可能是其易发乳腺癌的主要分子机制"的假说。本研究拟以临床调查和动物实验相结合的研究方法来对该假说进行验证。大样本的流行病学调查将被用于乳腺癌患者和健康志愿者体质类型分布规律的比较研究，以期客观公正地考察阴虚气郁体质对乳腺癌发病的影响；而动物实验除系统评价阴虚气郁状态对大鼠乳腺癌诱导模型的促发作用外，还将观察其对诱发癌组织中mTOR信号通路活化及PKM2表达的影响。研究结果不仅会明确阴虚气郁体质是否为乳腺癌发病的独立危险因素,而且将从整体及分子水平揭示以中医体质理论阐释乳腺癌发病机理的合理性与科学性，这对继而探寻相应的中医药预防措施大有裨益。

中医体质被认为与疾病的发生密切相关。本课题前期提出阴虚气郁可能为乳腺癌的易发体质的科研假说。为客观评价中医体质对乳腺癌发病的作用。本研究分别采用临床调查和实验研究考察阴虚气郁体质对乳腺癌发生发展的作用。.临床调查采用回顾、对照的横断面研究方法。体质评估主要采用王琦的中医体质评价量表。305例健康志愿者和305例乳腺癌患者被纳入该项研究，调查结果发现乳腺癌患者的四种偏颇体质（气郁体质、气虚体质、湿热体质和阴虚体质）的比例明显高于健康志愿者（p值均小于0.05）。逐步logistic回归分析结果显示只有气郁体质与乳腺癌呈高度正相关（OR=3.21, CI 1.49-6.92）。此外，当气郁体质和湿热体质兼夹，或与血瘀体质兼夹时，这种相关性增加（OR=4.82, CI 1.83-12.71；OR=3.27, CI 1.31-8.16）。而且，当湿热体质与血瘀体质兼夹时，也与乳腺癌的发生紧密相关（OR=2.88, CI 1.02-8.17）。表明气郁体质可能是乳腺癌发生的独立危险因素。血瘀体质、湿热体质、气郁体质相互兼夹时，可增加罹患乳腺癌的风险。提示中医偏颇体质可作为乳腺癌易感性的鉴别指标，将中医体质辨识作为区分乳腺癌易感人群及开发相应预防手段是可行的。.实验研究的目的是通过动物实验探讨阴虚气郁状态对乳腺癌发病的影响，及其可能的分子机制。对大鼠采用长期激怒法（分别激怒8周和22周）模拟人的阴虚气郁状态，观察其对发瘤率和潜伏期的影响，以及对肿瘤组织中PI3K、AKT、mTOR、HIF-1α、PKM2蛋白和基因表达的影响。结果发现激怒可以提高发瘤率（DMBA组、8周激怒+DMBA组与22周激怒+DMBA组的乳腺肿瘤诱发率分别为42.86%、53.57%和57.14%），但无统计学差异（P>0.05）；22周激怒+DMBA组的潜伏期较另两组缩短，但也无统计学差异（P>0.05）。三组间在PI3K、AKT、mTOR、HIF-1α、PKM2蛋白和基因表达方面无统计学差异。研究结果不支持激怒对肿瘤发生有促进作用，也不支持PI3K/AKT/mTOR信号通路的过度活化及PKM2的高表达为其作用机制的假说。基因测序的结果提示激怒应激对一些免疫相关基因的表达影响更为明显，而这很可能是其产生作用的机制所在。