共刺激分子CD40与多种恶性肿瘤及自身免疫病的发生发展存在关联。ER、PR、Her-2表达均为阴性的三阴乳腺癌（TNBC）患者易发生局部复发和远处转移，对传统的内分泌治疗和Her-2靶向治疗无效。我们前期研究发现，CD40基因5'-UTR rs1883832单核苷酸多态性（SNP）与中国东北部汉族女性乳腺癌发生风险、临床病理特点及预后显著相关，并影响CD40分子在真核细胞表达水平。据此推测rs1883832通过影响患者多种细胞CD40表达及CD40通路激活途径参与TNBC发生、发展。本项目研究CD40基因rs1883832三种基因型TNBC患者外周血髓系抑制性细胞（MDSC）免疫抑制作用及肿瘤细胞生物学特点间的差异，以此阐明CD40基因多态性、外周血MDSC及肿瘤细胞生物学特点、TNBC三者间的关联。本项目为rs1883832位点作为新的预测TNBC发生、预后的生物学标志提供依据。

Costimulatory molecule CD40 contributes to the occurrence and development a variety of malignancies and autoimmune diseases. Traditional endocrine and Her-2 targeted therapy have limited effects on ER-PR-Her-2- triple-negative breast cancer (TNBC) presenting as an aggressive disease-recurring and metastasizing more often than other kinds of breast cancer. Previously, we found that CD40 gene 5'-UTR single nucleotide polymorphism (SNP) rs1883832 which affected CD40 expression on eukaryotic cells was significantly associated with the risk, clinicopathologic features, and prognosis of breast cancer in Chinese Han population of Northeast China. We hypothesized that rs1883832 was involved in TNBC development by influencing CD40 expression and CD40 signal pathway activation on many cells. The project aims to confirm the individual discrepancies on peripheral myeloid-derived suppressor cells (MDSC) immunosuppression and biological characteristics of tumor cells among TNBC patients with different rs1883832 genotypes and hence clarify the relationship of CD40 polymorphism, biological characteristics of peripheral MDSC and tumor cells, and TNBC. This study may.provide basis for rs1883832 as a new biomarker in TNBC prediciton.

共刺激分子CD40与多种恶性肿瘤及自身免疫性疾病的发生、发展存在关联。本课题在前期流行病学研究基础上探究了CD40基因5’-UTR区域单核苷酸多态性位点rs1883832基因型、乳腺癌患者外周血MDSC及肿瘤细胞等多种细胞表面CD40表达、乳腺癌患者临床病理特点及预后三者之间的关联。研究发现，CD40基因5’-UTR 区域rs1883832 位点调控CD40 分子在体外真核细胞以及在人体外周血PBMC表面CD40分子表达水平；rs1883832位点多态性与包括TNBC在内乳腺癌患者肿瘤细胞表面CD40分子表达、患者临床病理特点及生存期之间存在关联；乳腺癌患者原位肿瘤组织与配对淋巴结转移灶肿瘤组织CD40表达存在显著差异；重组CD40L在体外可能通过参与调控mmp2、mmp9等分子表达途径影响TNBC细胞系MDA-MB-231迁移、侵袭能力。以上结果为rs1883832位点作为新的预测乳腺癌（包括TNBC亚分类）发生、预后的生物学标志提供理论依据。