Abstract
BackgroundAccumulating evidences indicate that the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) plays a key role in the development and progression of many human cancers. However, the underlying mechanism and prognosis value of SCUBE3 in breast cancer are still unclear.MethodsThe clinical data of 137 patients with breast cancer who underwent surgical resection in Taizhou Hospital of Zhejiang Province were retrospectively analyzed. We first conducted a comprehensive study on the expression pattern of SCUBE3 using the Tumor Immune Estimation Resource (TIMER) and UALCAN databases. In addition, the expression of SCUBE3 in breast tumor tissues was confirmed by immunohistochemistry. The protein–protein interaction analysis and functional enrichment analysis of SCUBE3 were analyzed using the STRING and Enrichr databases. Moreover, tissue microarray (TMA) was used to analyze the relationship between SCUBE3 expression levels and clinical-pathological parameters, such as histological type, grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). We further supplemented and identified the above results using the UALCAN and bc-GenExMiner v4.4 databases from TCGA data. The correlation between the expression of SCUBE3 and survival was calculated by multivariate Cox regression analysis to investigate whether SCUBE3 expression may be an independent prognostic factor of breast cancer.ResultsWe found that the expression level of SCUBE3 was significantly upregulated in breast cancer tissue compared with adjacent normal tissues. The results showed that the distribution of breast cancer patients in the high expression group and the low expression group was significantly different in ER, PR, HER2, E-cadherin, and survival state (p < 0.05), but there was no significant difference in histologic grade, histologic type, tumor size, lymph node metastasis, TMN stage, subtypes, or recurrence (p > 0.05). In addition, the high expression of SCUBE3 was associated with relatively poor prognosis of ER- (p = 0.012), PR- (p = 0.029), HER2 + (p = 0.007). The multivariate Cox regression analysis showed that the hazard ratio (HR) was 2.80 (95% CI 1.20–6.51, p = 0.0168) in individuals with high SCUBE3 expression, and HR was increased by 1.86 (95% CI 1.06–3.25, p = 0.0300) for per 1-point increase of SCUBE3 expression.ConclusionsThese findings demonstrate that the high expression of SCUBE3 indicates poor prognosis in breast cancer. SCUBE3 expression may serve as a potential diagnostic indicator of breast cancer.
Highlights
Breast cancer is the most common malignancy tumor and the leading cause of cancer death in women [1, 2]
To identify the correlation between signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) expression and clinical characteristics of breast cancer patients, we investigated the relationship between SCUBE3 expression and prognosis of breast cancer in TMN (TMN1, TMN2, and TMN3), tumor size (T ≤ 2 cm and T ≥ 2 cm), lymph node ( ±), histologic grade, histologic type, estrogen receptor (ER) (ER + /ER−), progesterone receptor (PR) (PR + /PR−), HER2 status (HER2 + /HER2−), using the Kaplan–Meier survival curves based on hazard ratio (HR) and log-rank p-values [23]
The differential expression of SCUBE3 between the tumor and adjacent normal tissues in all The Cancer Genome Atlas (TCGA) tumors were shown in Fig. 1a, in which SCUBE3 was overexpressed in breast cancer, but with relatively low expression in bladder urothelial carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, prostate adenocarcinoma, and thyroid carcinoma
Summary
Breast cancer is the most common malignancy tumor and the leading cause of cancer death in women [1, 2]. Accumulating studies have shown that SCUBE3 is closely related to the invasion and metastasis of lung cancer It mainly triggers the TGF-β pathway, and promotes epithelial-mesenchymal transition (EMT) [11, 12] and tumor angiogenesis [13]. The survival time of NSCLC patients with high expression of SCUBE3 was significantly shorter than that of NSCLC patients with low expression of SCUBE3, which supports the expression of SCUBE3 as an independent prognostic factor of NSCLC [14] It is unclear whether and how SCUBE3 promotes breast cancer progression. Accumulating evidences indicate that the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) plays a key role in the development and progression of many human cancers. The underlying mechanism and prognosis value of SCUBE3 in breast cancer are still unclear
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