Overexpression of MUC1 predicts poor prognosis in patients with breast cancer

Abstract

Breast cancer is the most commonly diagnosed cancer in females; thus, there is an urgent requirement to identify precise biomarkers for the diagnosis and treatment of the disease. Mucin 1 (MUC1) is a glycoprotein that has been demonstrated to be involved in the metastasis and invasion of multiple tumor types. Bioinformatics analyses were conducted to indicate the prognostic value of MUC1 in breast cancer. Additionally, the expression level of MUC1 was assessed using Oncomine analysis. Furthermore, PrognoScan was used to analyze the prognostic value of MUC1 in breast cancer. Mutations of MUC1 were analyzed by the Catalogue of Somatic Mutations in Cancer and cBioPortal databases. In addition, University of California, Santa Cruz (UCSC) was used to examine the methylation status of MUC1. Co‑expression of MUC1 mRNA was detected with the cBioPortal, UCSC and Breast Cancer Gene‑Expression Miner v4.0 datasets. The results demonstrated that MCU1 is frequently overexpressed in breast cancer and is negatively associated with CpG sites. Furthermore, pooled data indicated that abnormally high expression of MUC1 indicates poor prognosis. Additionally, upregulation of MUC1 expression is associated with estrogen receptor‑ and progesterone receptor‑positive disease, aging and increased Scarff, Bloom and Richardson grade, but is not associated with triple‑negative and basal‑like status. Subsequent data mining across multiple large databases demonstrated a positive association between MUC1 mRNA expression and cyclic AMP‑responsive element‑binding protein 3‑like 4 (CREB3L4) in breast cancer tissues. The present data indicated that the overexpression of MUC1 indicates a poor prognosis in patients with breast cancer and is associated with MUC1 promoter methylation status. Additionally, MUC1 positively correlated with CREB3L4 and may serve as a potential prognostic factor and therapy target for breast cancer.

Figure 1.

Pooled analyses on the mRNA expression of MUC1 in various carcinoma types. The mRNA expression of MUC1 (cancer vs. corresponding normal tissue) was evaluated using the Oncomine database (red represents significant overexpression and blue represents reduced expression). The following parameters were used as thresholds: P<1×10⁻⁴, fold-change >2 and gene ranking in the top 10%. CNS, central nervous system; MUC1, mucin 1.

Figure 2.

Analysis of MUC1 gene expression of the patients with breast cancer using the Oncomine database. Box plot derived from gene expression data in the Oncomine database comparing the expression of specific MCU1 in normal tissue and cancer tissue. Invasive breast carcinoma, invasive ductal breast carcinoma, mixed lobular and ductal breast carcinoma, invasive lobular breast carcinoma, intraductal cribriform breast adenocarcinoma, and invasive ductal and lobular carcinoma were included in the box plots. MUC1, mucin 1.

Figure 3.

(A) MCU1 gene expression heatmap and its DNA methylation status. (B) MUC1 expression in different breast cancer DNA methylation clusters (1–5 represents different methylation clusters). Results were generated using the UCSC Xena browser based on data in TCGA. MUC1, mucin 1; HER2, human epidermal growth factor receptor 2. *P<0.01 vs. cluster 5 group.

Figure 4.

MCU1 mutation in human breast cancer. (A) The percentages of mutation types of MUC1 in breast cancer were revealed in a pie chart generated from the Catalogue of Somatic Mutations in Cancer database. (B) cBioPortal was used to analyze the alteration frequency of MUC1 mutations in breast cancer. The data used included: The MBC Project (38); Breast (METABRIC) (30); breast (BCCRC Xenograft; British Columbia) (31); breast cancer (TCGA; provisional); breast invasive carcinoma (TCGA) (32); MBL (33); breast invasive carcinoma (TCGA; provisional); MSKCC/Breast 2015: Adenoid cystic carcinoma of the breast (MSKCC) (34); BCCRC 2012: Breast invasive carcinoma (British Columbia) (35); Broad 2012: Breast invasive carcinoma (Broad) (36); Sanger: Breast invasive carcinoma (Sanger) (37). MUC1, mucin 1; CNVs, copy number variations; MBC, metastatic breast cancer; METBRIC, Molecular Taxonomy of Breast Cancer International Consortium; TCGA, The Cancer Genome Atlas; BCCRC, BC Cancer Research Centre; MSKCC, Memorial Sloan Kettering Cancer Center.

Figure 5.

Association between MUC1 gene expression and clinical pathological parameters in patients with breast cancer. Notable global differences between the groups were evaluated by Welch's t-test to generate the P-value. MUC1, mucin 1; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; SBR, Scarff, Bloom and Richardson; TNBC, triple-negative breast cancer; IHC, immunohistochemistry.

Figure 6.

Prognostic significance of mucin 1 gene expression in patients with breast cancer (OS, RFS and DSS time in the PrognoScan database). OS, overall survival; RFS, relapse-free survival; DSS, disease-specific survival; HR, hazard ratio.

Figure 7.

MCU1 gene expression is associated with CREB3L4 gene expression in breast cancer. (A) The top 20 genes positively associated with MCU1 transcript level based on TCGA among ~482 patients with breast cancer. (B) Through regression analysis, it was determined that MUC1 and CREB3L4 were highly correlated. (C) Data mining in Breast Cancer Gene-Expression Miner v4.0 further confirmed the positive correlation of MCU1 and CREB3L4 mRNA expression. (D) A heatmap derived from University of California, Santa Cruz Xena revealed the MUC1 and CREB3L4 mRNA expression levels among PAM50 breast cancer subtypes in TCGA database. (E) Association between MUC1 and CREB3L4 gene expression in TCGA database. TCGA, The Cancer Genome Atlas; MUC1, mucin 1; HER2, human epidermal growth factor receptor 2; CREB3L4, cyclic AMP-responsive element-binding protein 3-like 4.

Figure 8.

CREB3L4 analysis in breast cancer (Oncomine database). Box plot derived from gene expression data in Oncomine comparing the specific CREB3L4 expression levels in normal and cancer tissues. There are two invasive lobular breast carcinoma datasets from different databases included. CREB3L4, cyclic AMP-responsive element-binding protein 3-like 4.

Figure 9.

Prognostic value of mRNA level of cyclic AMP-responsive element-binding protein 3-like 4 in patients with breast cancer (RFS and DSS time in the PrognoScan database). RFS, relapse-free survival; DSS, disease-specific survival; HR, hazard ratio.