Abstract
The expression of ANO1 is considered to have diagnostic specificity for gastrointestinal stromal tumors. However, its function as a calcium-activated chloride channel suggests that the expression of ANO1 is not restricted to gastrointestinal stromal tumors. Recently, it has been reported that ANO1 has roles in the progression of human malignant tumors. However, the role of ANO1 in breast carcinoma has been controversial. Therefore, we investigated the expression of ANO1 in 139 breast carcinoma patients and the role of ANO1 in vitro. The immunohistochemical expression of ANO1 was significantly associated with the expression of β-catenin, cyclin D1, MMP9, snail, and E-cadherin. Especially, ANO1 expression was an independent indicator of poor prognosis of shorter overall survival and relapse-free survival of breast carcinoma patients by multivariate analysis. In MCF7 and MDA-MB-231 breast carcinoma cells, inhibition of ANO1 with T16Ainh-A01 or siRNA for ANO1 significantly suppressed the proliferation of cells. Knock-down of ANO1 with siRNA induced G0/G1 cell cycle arrest and significantly inhibited the invasiveness of breast carcinoma cells. Knock-down of ANO1 decreased the expression of β-catenin, cyclin D1, MMP9, snail, and N-cadherin, and increased the expression of E-cadherin. In conclusion, this study demonstrates that ANO1 expression is an indicator of poor prognosis of breast carcinoma patients and suggests that ANO1 might be a therapeutic target for breast carcinoma patients with ANO1-positive tumors and poor prognosis.
Highlights
ANO1 is a member of the TMEM16 family and characterized by its role as a calcium-activated chloride channel [1]
Immunohistochemical expression of ANO1, β-catenin, MMP9, snail, and E-cadherin were observed in the cytoplasmic membrane, cytoplasm, and nuclei of tumor cells and the expression of cyclin D1 was observed in the nuclei of tumor cells (Figure 1)
The cut-off points for the MMP9, snail, and E-cadherin expression were seven (Figure 1)
Summary
ANO1 is a member of the TMEM16 family and characterized by its role as a calcium-activated chloride channel [1]. The possibility that ANO1 might be involved in the tumorigenesis has been suggested by its chromosomal location at 11q13 because this loci is frequently amplified in various human malignant tumors, such as head and neck cancer, breast carcinoma (BCA), lung cancer, and esophageal cancer [8]. Higher expression of ANO1 was significantly associated with advanced phenotypes of prostatic carcinomas [11] and oral squamous cell carcinomas [13]. The expression of ANO1 was significantly correlated with shorter survival of gastric carcinomas [9] and head and neck squamous cell carcinomas [14]. It has been suggested that ANO1 is involved in tumorigenesis by either its role as a calcium-dependent chloride channel or as a signaling molecules. Further study is needed to clarify the exact role of ANO1 in human malignant tumors
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