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Triple-Negative Breast Cancer with High Levels of Annexin A1 Expression Is Associated with Mast Cell Infiltration, Inflammation, and Angiogenesis.

ABSTRACT: Annexin A1 (ANXA1) is a phospholipid-linked protein involved in inflammation, immune response, and mast cell reactivity. Recently, we reported that ANXA1 is associated with aggressive features of triple-negative breast cancer (TNBC); however, its clinical relevance remains controversial. We hypothesized that human TNBC with high expression of ANXA1 mRNA is associated with pro-cancerous immune cell infiltration, including mast cells, and with an aggressive phenotype. Clinical and RNA-seq data were obtained from The Cancer Genome Atlas (TCGA, n = 1079) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1904). TNBC patients had significantly higher levels of ANXA1 expression compared to the other subtypes in both TCGA and METABRIC cohorts (p < 0.001). ANXA1 protein expression was assessed by immunohistochemistry in Japanese TNBC patient cohort (n = 48), where 17 cases (35.4%) had positive ANXA1 staining, and their overall survival was significantly shorter compared with negative staining group (p = 0.008). The CIBERSORT algorithm was used to calculate immune cell infiltrations. ANXA1 high tumors were associated with activated mast cells and M2 macrophages (p > 0.01), but did not show any association with tumor heterogeneity nor cytolytic activity. High expression of ANXA1 group enriched inflammation, epithelial-to-mesenchymal transition (EMT), and angiogenesis-related genes in a gene set enrichment assay in both cohorts. To our knowledge, this is the first study to demonstrate that ANXA1 is associated with infiltration of mast cells and inflammation that is associated with the aggressive phenotype of TNBC, such as EMT and angiogenesis.

SUBMITTER: Okano M

PROVIDER: S-EPMC6747082 | biostudies-other | 2019 Aug

REPOSITORIES: biostudies-other

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Triple-Negative Breast Cancer with High Levels of Annexin A1 Expression Is Associated with Mast Cell Infiltration, Inflammation, and Angiogenesis.

Okano Maiko M Oshi Masanori M Butash Ali Linsk AL Katsuta Eriko E Tachibana Kazunoshin K Saito Katsuharu K Okayama Hirokazu H Peng Xuan X Yan Li L Kono Koji K Ohtake Toru T Takabe Kazuaki K

International journal of molecular sciences 20190827 17

Annexin A1 (ANXA1) is a phospholipid-linked protein involved in inflammation, immune response, and mast cell reactivity. Recently, we reported that ANXA1 is associated with aggressive features of triple-negative breast cancer (TNBC); however, its clinical relevance remains controversial. We hypothesized that human TNBC with high expression of ANXA1 mRNA is associated with pro-cancerous immune cell infiltration, including mast cells, and with an aggressive phenotype. Clinical and RNA-seq data wer ...[more]

PMID: 31461932

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Project description:BACKGROUND:Limited information is available on biomarker(s) for triple-negative breast cancer (TNBC) that can address the higher incidence and aggressiveness of TNBC in African-American (AA) women. Our previous studies have demonstrated annexin A2 (AnxA2) association with exosomes which promotes angiogenesis and metastasis. Therefore, our goal was to examine the expression and function of exosomal-annexin A2 (exo-AnxA2) derived from the serum samples of breast cancer patients. METHODS:The expression of serum exo-AnxA2 and its association with clinicopathological features of the breast cancer patients were determined. The role of serum exo-AnxA2 to promote angiogenesis was determined by an in vivo Matrigel plug assay. RESULTS:Our results show that the expression of serum exo-AnxA2 in breast cancer patients (n?=?169; 83.33?±?2.040?ng/mL, P?<?0.0001) is high compared to non-cancer females (n?=?68; 34.21?±?2.238?ng/mL). High expression of exo-AnxA2 levels in breast cancer was significantly associated with tumor grade (P?<?0.0001), poor overall survival (hazard ratio (HR) 2.802; 95% confidence intervals (CI)?=?1.030-7.620; P?=?0.0353), and poor disease-free survival (HR 7.934; 95% CI?=?1.778-35.398; P?=?0.0301). The expression of serum exo-AnxA2 levels was significantly elevated in TNBC (n?=?68; 109.1?±?2.905?ng/mL; P?<?0.0001) in comparison to ER+ (n?=?50; 57.35?±?1.545?ng/mL), HER2+ (n?=?59; 78.25?±?1.146?ng/mL), and non-cancer females (n?=?68; 34.21?±?2.238?ng/mL). Exo-AnxA2 showed diagnostic values with a maximum AUC as 1.000 for TNBC, 0.8304 for ER+, and 0.9958 for HER2+ compared to non-cancer females. The expression of serum exo-AnxA2 was significantly elevated in AA women with TNBC (n?=?29; 118.9?±?4.086?ng/mL, P?<?0.0001) in comparison to Caucasian-American TNBC (n?=?27; 97.60?±?3.298?ng/mL) patients. Our in vivo results suggest a role of serum exo-AnxA2 in angiogenesis and its association with aggressiveness of TNBC in AA women. CONCLUSIONS:Our results demonstrated that the expression of serum exo-AnxA2 is high in AA women with TNBC and promotes angiogenesis. These findings suggest that exo-AnxA2 holds promise as a potential prognosticator of TNBC and may lead to an effective therapeutic option.

Dataset Information

Triple-Negative Breast Cancer with High Levels of Annexin A1 Expression Is Associated with Mast Cell Infiltration, Inflammation, and Angiogenesis.

Publications

Triple-Negative Breast Cancer with High Levels of Annexin A1 Expression Is Associated with Mast Cell Infiltration, Inflammation, and Angiogenesis.

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