Abstract
Breast cancer remains a leading cause of cancer-related death, for which the majority of deaths result from metastases. Von Willebrand factor C and EGF domain (VWCE) is a member of the Von Willebrand factor (VWF) gene family; however, its function, regulatory mechanism, and clinical value in breast cancer remain unclear. In the present study, we sought to elucidate the role of VWCE in breast cancer metastasis. We examined the expression of VWCE in breast cancer tissues and normal control tissues of 50 breast cancer patients. We found that VWCE expression was downregulated in breast cancer cells and tissues compared to normal breast epithelial cells or the adjacent normal tissues. To explore the role of VWCE in human breast cancer development, we introduced a VWCE-overexpressing or control lentiviral vector into the breast cancer MDA-MB-453 and MDA-MB-231 lines in vitro. The overexpression of VWCE inhibited the proliferation, migration, invasion, and chemoresistance of the breast cancer cell lines. More importantly, the forced expression of VWCE suppressed tumor formation and metastasis in nude mice. iTRAQ-based quantitative proteomic analysis revealed that VWCE overexpression induced a 10-fold decrease in the level of WD-repeat domain 1 (WDR1) protein expression. Rescue experiments further verified that WDR1 was a downstream molecule of VWCE, and WDR1 overexpression reversed the above effects of VWCE overexpression on tumor growth. Therefore, VWCE may represent a novel tumor suppressor, for which its deregulation promotes breast cancer progression via the upregulation of WDR1.
Highlights
Breast cancer is the most common type of cancer affecting women worldwide and the leading cause of cancer-related death in women [1]
We first analyzed the level of Von Willebrand factor C and EGF domain (VWCE) expression in breast cancer tissues and cultured the breast cancer cell lines using Quantitative real-time RT-PCR (qRT-PCR), immunohistochemistry, and Western blot
Using qRT-PCR, we assessed the level of VWCE mRNA expression in 50 human breast cancer specimens relative to 50 normal breast tissue samples, and VWCE mRNA is highly expressed in normal tissues adjacent to the tumor (Figure 1B); in contrast, the expression in breast cancer tissue is lower
Summary
Breast cancer is the most common type of cancer affecting women worldwide and the leading cause of cancer-related death in women [1]. The role of VWCE has been studied in several types of tumors. VWCE has been found to be highly expressed in hepatocellular carcinoma, gastric cancer, pancreatic cancer, and lung cancer, and is associated with increased invasion and metastasis of these tumor cells [13,14,15,16,17,18]. BMP signal transduction mediated by a new peptide agonist, P123, leads to the reversal of the epithelial-mesenchymal transition process in human breast cancer stem cells and inhibits selfrenewal and growth, thereby slowing the invasion and metastasis of breast cancer [12]. The expression and function of VWCE in breast cancer cells are studied, and the possible anti-tumor mechanisms are further explored
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