肿瘤中的巨噬细胞与ER-乳腺癌的强耐药性、高转移且预后差的恶性性状密切相关。我们的研究显示，CD151可能参与对这类细胞的调控：1)敲除CD151不仅抑制乳腺癌的生长和转移， 而且导致肿瘤中巨噬细胞的减少。作为巨噬细胞的重要调节分子，TAMR(TAM家族受体赖氨基酸激酶) 的表达也受到抑制；2)与TAMR功能相近的Ron，不仅通过巨噬细胞影响肿瘤的恶化和转移，而且也受CD151调控。因此，我们假设：CD151通过与TAMR和Ron形成蛋白复合体来调控巨噬细胞，从而促进乳腺癌的生长和恶化。为检验这一假设，我们将：1)鉴定CD151在巨噬细胞入侵肿瘤过程中的关键作用；2)诠释CD151复合体对巨噬细胞促癌转移功能的调控机制；3)评估CD151复合体调控巨噬细胞的临床意义。本课题旨在阐明CD151复合体在肿瘤微环境中的作用，揭示乳腺癌恶性的机理，为其精准诊断与治疗提供新的生物学依据和靶点。

The malignancy of human ER- breast cancer is strongly associated with intrinsic drug resistance, rapid tumor progression and high metastatic potential. These aggressive traits are increasingly linked to the action of tumor-associated macrophages. Thus, identifying pivotal regulators of this set of stromal cells within tumor microenvironments will be crucial for the improvement in the diagnosis and treatment of ER- breast cancer. Our recent studies have demonstrated that CD151, a member of tetraspanin family, along with its associated laminin-binding (LB) integrins, is strongly linked to macrophage-mediated tumor growth and progression in breast cancer. Notably, deletion of CD151 in the MMTV-Wnt1 or MMTV-ErbB2 model markedly impairs mammary tumor growth, invasion and pulmonary metastasis. These functional effects of CD151 deletion are accompanied by a marked reduction in the number of tumor-infiltrating macrophages, and a concomitant downregulation of TAM family receptor tyrosine kinases (TAMR), including Axl, Mer and Tyro3, and their ligand Gas6. Meanwhile, we have found that Ron, a close relative of TAMR, forms tight protein complexes with CD151 and LB integrins. Ron is also implicated in promoting the pro-metastatic phenotype of tumor-associated macrophages. Based on this evidence, we hypothesize that CD151 forms complexes with LB integrins and a set of receptor tyrosine kinases (TAMR and Ron), that is, CD151/L/R protein complexes, to drive stromal infiltration and pro-metastatic phenotype of tumor-associated macrophages to accelerates breast cancer development, progression and metastasis. To test this hypothesis, we will conduct following aims: Aim 1. Investigate how CD151 promotes mammary tumorigenesis through recruitment of tumor-associated macrophages and activation of TAMR; Aim.2. Delineate molecular mechanisms underlying which CD151 drives the Ron-dependent pro-metastatic phenotype of tumor-associated macrophages; Aim 3. Assess the link of CD151-mediated macrophage activity and phenotype to drug resistance of breast tumors, and correlation with key clinical parameters, including tumor grade and stage, as well as patient response to treatment. Our proposed study aims to define a pivotal role of CD151 and its protein complexes in tumor-associated macrophages during breast cancer development and progression. We predict data from our project will provide key molecular and biological bases for development of novel biomarkers and therapeutic targets to improve diagnosis and treatment of human ER- breast cancer。