Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Cancer Med. 2020 Dec;9(24):9554-9570. doi: 10.1002/cam4.3543. Epub 2020 Oct 14.
Breast cancer (BC) poses one of the major threats to female's health worldwide. Immune infiltration in BC is a key representative of the tumor microenvironment and has been proven highly relevant for prognosis. The role of the FREM1 (FRAS1-Related Extracellular Matrix 1) gene in carcinoma has not studied, moreover, the underlying mechanism remains largely unknown. This study aims to investigate the expression profile and potential action of FREM1 on BC progression. We applied series of bioinformatic methods as well as immunohistochemistry (IHC) and immunofluorescence (IF) to analyze FREM1 expression profile, its relationship with clinicopathological characteristics, impact on clinical outcomes, relevant functions, correlation with immune infiltration in BC. The results demonstrated that FREM1 had a dramatically reduced expression in BC tissues, possessed an inverse correlation with stage, age, and metastasis, and exhibited a higher level in invasive lobular breast carcinoma than in ductal one. Furthermore, decreased FREM1 expression was often associated with estrogen receptor (ER)/progesterone receptor (PR) negative and triple negative breast carcinoma (TNBC) status while human epidermal growth factor 2 (Her-2) positive status, and considerably correlated with a worse overall survival (OS) and recurrence-free survival (RFS). Meanwhile, the univariate/multivariate Cox model revealed that low-FREM1 expression can be an independent prognostic factor for BC. Additionally, FREM1 was mainly involved in the cell metabolism and immune cells infiltration. Moreover, IHC and IF demonstrated a positive correlation of its expression with the immune infiltrating levels of CD4 , CD8 T cells, and CD86 M1 macrophages while a negative correlation with CD68 pan-macrophages and CD163 M2 macrophages. These findings suggest that FREM1 can be a potential biomarker for evaluating the immune infiltrating status, and the BC prognosis.
乳腺癌（BC）是全球女性健康的主要威胁之一。BC 中的免疫浸润是肿瘤微环境的一个关键代表，已被证明与预后高度相关。FREM1（FRAS1 相关细胞外基质 1）基因在癌中的作用尚未研究，其潜在机制也知之甚少。本研究旨在探讨 FREM1 在 BC 进展中的表达谱和潜在作用。我们应用了一系列生物信息学方法以及免疫组织化学（IHC）和免疫荧光（IF）来分析 FREM1 的表达谱、它与临床病理特征的关系、对临床结局的影响、相关功能以及与 BC 中免疫浸润的相关性。结果表明，FREM1 在 BC 组织中的表达显著降低，与分期、年龄和转移呈负相关，在浸润性小叶乳腺癌中的表达高于在导管癌中。此外，FREM1 表达降低通常与雌激素受体（ER）/孕激素受体（PR）阴性和三阴性乳腺癌（TNBC）状态相关，而与 Her-2 阳性状态相关，与总体生存（OS）和无复发生存（RFS）较差显著相关。同时，单变量/多变量 Cox 模型显示，低 FREM1 表达可作为 BC 的独立预后因素。此外，FREM1 主要参与细胞代谢和免疫细胞浸润。此外，IHC 和 IF 显示其表达与 CD4、CD8 T 细胞和 CD86 M1 巨噬细胞的免疫浸润水平呈正相关，与 CD68 泛巨噬细胞和 CD163 M2 巨噬细胞呈负相关。这些发现表明，FREM1 可能是评估免疫浸润状态和 BC 预后的潜在生物标志物。
