Abstract
The calcium-activated chloride channel Ano1 (TMEM16A) is overexpressed in many tumors. However, conflicting data exist regarding the role of Ano1 in cell proliferation. Here, we performed immunohistochemistry to investigate the expression of Ano1 and Ki67 in 403 patients with breast cancer, and analyzed the association between the expression of Ano1 and Ki67 in breast cancer subtypes categorized according to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Ano1 expression was negatively correlated with Ki67 expression. Ano1 overexpression more frequently occurred in ER-positive or HER2-negative patients with the low expression of Ki67. Ano1 overexpression was associated with longer overall survival (OS) in breast cancer with the low expression of Ki67, especially in ER-positive, PR-positive, and HER2-negative breast cancer. Multivariate Cox regression analysis showed that Ano1 overexpression was a prognostic factor for longer overall survival in ER-positive, PR-positive, or HER2-negative patients with the low expression of Ki67. Furthermore, Ano1 promoted cell proliferation in ER-positive, PR-positive, and HER2-negative MCF7 cells, but inhibited cell proliferation in ER-negative, PR-negative, and HER2-negative MDA-MB-435S cells. Our findings suggest that Ano1 may differentially regulate cell proliferation in a subtype of breast cancer defined by ER, PR, and HER2. Combined expression of Ano1 and Ki67 may be used for predicting clinical outcomes of breast cancer patients with different subtypes of ER, PR, and HER2.
Highlights
Anoctamin 1 (Ano1, TMEM16A) is a novel calcium-activated chloride channel (CaCC) identified by three independent laboratories in 2008 [1,2,3]
We have previously found that Ano1 overexpression is associated with good prognosis in PRpositive or human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients following tamoxifen treatment [19]
We investigated the cell-specific mechanisms of Ano1 in breast cancer cell proliferation in breast cancer tumors and cell lines with different estrogen receptor (ER), progesterone receptor (PR) and HER2 status
Summary
Anoctamin 1 (Ano, TMEM16A) is a novel calcium-activated chloride channel (CaCC) identified by three independent laboratories in 2008 [1,2,3]. Before the discovery of Ano as a CaCC, Ano has been found to be overexpressed in many cancers including gastrointestinal stromal tumor, esophageal squamous www.impactjournals.com/oncotarget cell cancer, and head and neck squamous cell carcinoma (HNSCC) [13,14,15,16]. Amplification of the corresponding chromosomal region in 11q13 contributes to Ano overexpression in many cancers including breast cancer [18, 24,25,26]. The 11q13 amplification only occurs in approximately 15% of breast cancer patients [27]. It is unlikely that the 11q13 amplification is the only contributor to Ano overexpression in breast cancer. It has been reported that the inhibition of histone deacetylase (HDAC) downregulated Ano expression in breast cancer cells, suggesting that epigenetic regulation of Ano by HDAC may contribute to Ano overexpression in breast cancer [28]. Our previous study have shown that in ER-negative breast cancer, Ano expression was higher in PR-positive tumors than in PR-negative tumors, suggesting that Ano expression may be regulated by the ER/PR signaling pathway [19]
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