Abstract
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.
Highlights
Breast cancer (BC), the malignant condition with the highest incidence worldwide, is one of the leading causes of cancer-related death in women worldwide
We explore the effect of FRAS1-Related Extracellular Matrix 1 (FREM1) on the distribution of immune cells in BC patients with different molecular subtypes (Luminal, Human Epidermal Growth Factor Receptor-2 (Her-2) overexpression and triple negative breast cancer [triple negative breast carcinoma (TNBC)])
FREM1, known as QBRICK, is a secreted matrix-related protein encoded by the FREM1 gene located at the chromosome 9p22.3.10 A ternary complex formed by it with FRAS1 and FREM2 from the same family is responsible for maintaining the stability of the cell basement membrane.[30]
Summary
Breast cancer (BC), the malignant condition with the highest incidence worldwide, is one of the leading causes of cancer-related death in women worldwide. A novel target for the treatment and the identification of prognostic markers are of great significance for reducing BC patient's mortality
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