中医认为“肾阳亏虚、冲任失调为本，痰瘀毒结乳络为标”是乳岩病机核心，前期工作基础示温阳化痰方阳和化岩汤能抑制癌变进程中PI3K/AKT通路PI3K活化及脉管（微血管/淋巴管）生成。HER-2介导的微血管/淋巴管新生、侵袭是乳腺癌HER-2过表达者高增殖、高转移、预后差的分子机制，本课题建立HER-2高表达型乳腺癌细胞株SK-BR-3及裸鼠移植瘤模型，从体内、体外实验验证中药抑制脉管生成（MVD、LVD）和侵袭作用(微血管、淋巴管侵犯(MVI、LVI))，对血管内皮运动、粘附迁移功能影响及对COX-2/VEGFA-C/VEGFR、PI3K/Akt交互调控通路中关键靶点PI3K、Akt、COX-2、抑制基因PTEN；HER-2 、Bcl-2、VEGF-A,-C,-D及受体VEGFR-1，-2，-3（Flt-4）蛋白和mRNA表达为靶点的多层次研究，揭示中药干预高侵袭性乳腺癌脉管生成和侵袭机制。

TCM believes that "kidney yang deficiency, Chongren imbalance as this, phlegm and Blood Stasis Toxin knot dairy complex as the standard" is the core of breast cancer pathogenesis, progress and metastasis and recurrence, the display of Warming Yang Huatan Fang Yang and rock decoction can inhibit the carcinogenesis of PI3K/AKT pathway in the activation of PI3K and vasculogenesis (micro vascular, lymphatic vessel density). Microvascular / HER-2 mediated lymphangiogenesis and vascular invasion is an important molecular mechanism of breast cancer HER1-2 overexpression in patients with high proliferation, metastasis, prognosis is poor, the high expression of HER-2 SK-BR-3 and transplanted tumor in nude mice model of breast cancer cell lines, from in vivo, in vitro experimental verification and rock soup inhibited vascular (micro vascular and lymphatic invasion () generation and microvascular invasion (MVI) and lymphatic vessel invasion (LVI)), and the key targets of HER-2 mediated COX-2/VEGFA-C/VEGFR, PI3K/Akt interactive regulation signal pathway in PI3K, Akt, COX-2, PTEN, HER-2, Bcl-2 suppressor gene, VEGF-A, -C, -D and related receptor VEGFR-1, -2, -3 (Flt-4) protein and mRNA expression for multilevel research target, from the HER-2 mediated COX-2/VEGFA-C/VEGFR pathway, PI3K/Akt pathway of Chinese medicine to the high expression of HER-2 in breast cancer micro vessel / lymphangiogenesis and vascular invasion and intervention mechanism research, to explore the mechanisms of Chinese medicine on high invasive breast cancer control the occurrence, development and metastasis of malignant.

背景：Herb-2过表达型乳腺癌具有高趋化和高侵袭反应特性，组织血管/淋巴管生成迅速，脉管侵袭力强，针对HER-2过表达的靶向药物曲妥珠单抗仅对30%患者有效，HER-2介导的微血管/淋巴管新生、侵袭是乳腺癌HER-2过表达者高增殖、高转移、预后差的分子机制，温阳散结中药可望成为提高高侵袭性乳腺癌靶向治疗疗效的增效剂。方法：依据乳腺癌的病因病机肾虚冲任失调、寒痰瘀血凝结，依从论治法则温阳散结组方阳和化岩汤，制备中药含药肠吸收液，体内实验部分建立乳腺癌细胞株SK-BR-3裸鼠荷瘤模型，分对照组、阳和化岩汤组、曲妥珠单抗组、阳和化岩汤+曲妥珠单抗组、ly（PI3K抑制剂）组、ly+阳和化岩汤组6组，干预治疗4周观察裸鼠肿瘤出现情况，荧光免疫双染法观察在体成瘤实验各组血管生成情况，镜下观察LMVD数量，体外实验部分观察24h、48h、72h药物对细胞生长抑制率、细胞凋亡率和细胞周期，观察乳腺癌细胞与HUVEC血管共发生情况，transwell实验观察乳腺癌细胞穿内皮情况。体内外实验均用Western blot、RT-PCR法检测PTEN、AKT、p-AKT、COX-2、PI3K、HER-2、VEGFBCD、VEGFR的蛋白及mRNA表达量。结果：体内实验中，阳和化岩汤体现出了良好协同效果，与曲妥珠及ly联用，肿瘤重量有效减少，抑瘤率、淋巴结抑制率增加；荧光免疫双染法显示治疗组在体成瘤实验具有正常功能的血管数量及总血管数量均减少；LMVD数量明显减少；体外实验中中药能有效协同、增强曲妥珠及LY作用，增强抑制细胞增殖、诱导凋亡，增强S期阻滞。transwell显示穿过HUVEC内皮的细胞数量减少，均能抑制细胞迁移及侵袭，中药+曲妥珠组抑制抑制细胞穿内皮及形成脉管的效果最佳，体现了中药协同抑制细胞的迁移及侵袭作用;抑制PTEN-PI3K/AKT肿瘤生存信号通路活化，促进PTEN表达，抑制p-AKT、PI3K、HER-2、VEGFBCD、VEGFR蛋白及mRNA表达水平。结论：从抑制细胞增殖，诱导细胞凋亡、增强S期阻滞、抑制脉管系统从而抑制细胞的迁移及侵袭角度验证温阳散结中药在HER-2高表达型乳腺癌的治疗中能有效协同、增强曲妥珠及LY作用，作用机制与对微血管/淋巴管新生中关键信号通路——HER-2/VEGFA-C/VEGFR通路及PI3K/Akt交互调控通路的干预有关。