内分泌耐药是乳腺癌领域亟待解决的重要问题，既往研究集中在肿瘤细胞本身，但并不能从根本上解决问题。近年研究发现，肿瘤微环境对肿瘤侵袭转移及治疗效果起重要作用，但其对内分泌耐药的影响尚不清楚。前期研究发现在内分泌药物作用下，乳腺癌基质发生了显著改变，肿瘤细胞通过激活成纤维细胞，逐步建立肿瘤耐药基质。推测活化的成纤维细胞（CAFs）通过激活乳腺癌细胞导致内分泌耐药；乳腺癌细胞又可使巨噬细胞向M2型分化，再作用于肿瘤细胞加剧内分泌耐药进程。本项目拟通过体内外实验证实CAFs通过激活乳腺癌细胞内PI3K/AKT生长信号通路导致内分泌耐药；进而乳腺癌细胞通过CSF-1使巨噬细胞向M2型分化，增加EGF分泌，激活EGFR/MAPK信号通路，加剧乳腺癌细胞激素非依赖性生长。本研究将明确乳腺癌基质中的成纤维细胞在乳腺癌耐药中的关键作用及其机制，为从肿瘤基质入手逆转乳腺癌内分泌耐药提供理论依据和研究基础。

Endocrine resistance is an significant issue in the field of breast cancer research and treatment. Previous studies primary focus on the tumor cells themselves, but have not fundamentally solved the problem. Recent studies have found that tumor microenvironment might play an important role in tumor invasion, metastasis and therapeutic effects, but its impact on endocrine resistance in breast cancer is unclear. Our preliminary study found that endocrine resistant breast cancer was with stromal changing nature, especially in fibroblasts. Suggesting that tumor cells, through interaction with fibroblasts, gradually establish stromal tumor resistance, a process of endocrine resistance. And than breast cancer cells can make macrophages to M2 dimorphism, act on the tumor cells, exacerbate endocrine drug process. In this project we will determine whether the activated fibroblasts cause endocrine resistance through activation of PI3K/AKT growth signaling pathways in breast cancer cells in vitro and in vivo; CSF-1 breast cancer cells with macrophages M2-type differentiation increase EGF secretion and thus activate EGFR / MAPK signaling pathway, and exacerbate breast cancer cells in hormone-independent growth. This study relates to clear the tumor in the breast stromal fibroblasts key role in breast cancer resistance mechanisms, and provide a theoretical basis for the start reversing breast cancer endocrine resistance from the tumor microenvironment. Thus, our study might provide a novel strategy to resolve the endocrine resistance in breast cancer.

内分泌耐药是乳腺癌领域亟待解决的重要问题，既往研究集中在肿瘤细胞本身，但并不能从根本上解决问题。近年研究发现，肿瘤微环境对肿瘤侵袭转移及治疗效果起重要作用，但其对内分泌耐药的影响尚不清楚。内分泌药物作用下，乳腺癌基质发生了显著改变，肿瘤细胞通过激活成纤维细胞，逐步建立肿瘤耐药基质。推测活化的成纤维细胞（CAFs）通过激活乳腺癌细胞导致内分泌耐药；乳腺癌细胞又可使巨噬细胞向M2型分化，再作用于肿瘤细胞加剧内分泌耐药进程。本项目通过体内外实验证实.长期内分泌治疗使乳腺癌细胞分泌TGFβ增加,可诱导成纤维细胞表达FAP,进而分化成CAFs；CXCR4/SDF-1和CCR5/CCL5对CAFs和肿瘤细胞的趋化作用，形成纤维化灶，促进“耐药基质”形成；CAFs激活AKT旁分泌信号通路，导致乳腺癌内分泌耐药；内分泌耐药乳腺癌细胞分泌CSF-1增加, 刺激巨噬细胞从M1型向M2型分化；M2型巨噬细胞通过EGFR/MAPK信号通路，加剧乳腺癌细胞激素非依赖性生长。本研究明确乳腺癌基质中的成纤维细胞在乳腺癌耐药中的关键作用及其机制，为从肿瘤基质入手逆转乳腺癌内分泌耐药提供理论依据和研究基础。