乳腺癌弹性特征的细胞外基质调控机制的研究

Our previous study demonstrated that the elastic feature of tumor was correlated closely with the compositions of extracellular matrix (ECM), which demonstrated the important role of ECM in the regulation of tumor elasticity. TGF-β is an important factor in regulating ECM, but its influence on elasticity, its role in the regulation of breast carcinoma cells proliferation and invasiveness by ECM and the corresponding signal transduction way haven’t been deeply studied. Deeply studying the role of TGF-β and its signal transduction way could deepen the study of elasticity, clear the regulation mechanism of ECM and its influence on the elasticity, and provide the target for the treatment of breast cancer. .This study would deeply study the role of TGF-β on the influence of elasticity and in the regulation of breast carcinoma cells proliferation and invasiveness by ECM and the corresponding signal transduction way by cellular, tissue, animal studies with the methods of molecular biology and histopathology. This study would be helpful for: (1) further clearing the role of ECM on elasticity, and improve the early accurate diagnostic rate of breast carcinoma; (2) clearing the role of TGF-β in the regulation of breast carcinoma cells proliferation and invasiveness by ECM and the corresponding signal transduction way, through which TGF-β and its signal transduction molecular might become the therapeutic targets of breast carcinoma. This study would be of great medical significance.

本课题组前期研究表明，弹性成像在乳腺癌的诊断中具有重要意义，且弹性模量值与细胞外基质的组织学成分密切相关，证实细胞外基质在肿瘤弹性特征的调控中具有重要意义。TGF-β是调节肿瘤细胞外基质硬度的重要因素，但其对弹性特征的影响及其信号转导通路机制尚未见研究。深入探讨TGF-β对乳腺癌细胞外基质硬度及弹性特征的调控机制，可进一步深化乳腺癌弹性特征的研究，对于早期诊断、治疗具有重要意义。.本研究拟采用组织病理、分子生物学等方法，通过细胞、组织、动物实验深入探讨TGF-β对乳腺癌细胞外基质硬度、弹性特征的影响，以及乳腺癌细胞增殖和侵袭的过程中，TGF-β的调控作用及其可能的信号转导通路。本研究有助于：（1）进一步阐明乳腺癌弹性特征的细胞外基质调控机制，提高乳腺癌的早期正确诊断率；（2）明确TGF-β调控乳腺癌细胞外基质硬度及弹性特征的信号转导通路，有望为乳腺癌治疗提供新靶点，具有重要的医学价值。

乳腺癌严重危害女性健康，研究表明，乳腺癌早期诊断5年生存率可超过95%，因而早期发现、早期诊断十分重要。前期研究表明，弹性成像在乳腺癌的诊断中具有重要意义，且弹性模量值与细胞外基质密切相关，证实细胞外基质在肿瘤弹性特征的调控中具有重要意义。既往研究表明TGF-β是调节肿瘤细胞外基质硬度的重要因素，但其对乳腺病变弹性特征的影响及其信号转导通路机制尚少见研究。因而本研究采用剪切波弹性成像、组织病理等方法，通过免疫组化实验与半定量分析探讨TGF-β1、PI3K，Smad2/3，Erk1/2，JNK2，p38 MAPK，AKT等7种抗体的表达水平与乳腺病变临床资料，弹性特征，有、无腋下淋巴结转移之间的关系及PI3K，Smad2/3，Erk1/2，JNK2，p38 MAPK，AKT表达水平与TGF-β1表达水平之间的相关性，发现TGF-β1、Smad2/3、Erk1/2、p38 MAPK、JNK2、PI3K、AKT表达水平与最大、平均弹性模量值，SD值、病变与周围组织弹性比值、“硬环征”及腋下淋巴结转移等均具相关性，TGF-β1表达水平是影响乳腺病变最大、平均弹性模量值，SD值，病变与周围组织弹性比值及“硬环征”等的主要因素，Smad2/3、Erk1/2、p38 MAPK、JNK2、PI3K、AKT表达水平与TGF-β1表达水平亦具相关性，提示TGF-β1可能经由多条信号转导通路在乳腺病变的硬度调控过程中起重要作用，为后续探讨TGF-β1调控乳腺病变的弹性特征的可能的信号转导通路提供可靠资料，提高剪切波弹性成像在乳腺良、恶性病变鉴别诊断甚至治疗方面的临床应用价值，以期为乳腺病变的诊断与治疗提供新的切入点与思路。