Abstract
Naked cuticle homolog 2 (NKD2) has been reported to antagonize Wnt signaling in zebrafish, mouse and mammals. The aim of this study is to investigate the epigenetic changes and mechanisms of NKD2 in human breast cancer development. Six breast cancer cell lines (MCF-7, ZR75-1, MDA-MB-468, MDA-MB-231, T47D and BT474) and 68 cases of primary human breast cancer were studied using methylation specific PCR, immunohistochemistry, western blot, flow cytometry techniques and a xenograft mouse model. The expression of NKD1 and NKD2 was regulated by promoter region methylation in breast cancer cells. No NKD1 methylation was found in primary human breast cancer. NKD2 was methylated in 51.4% (35/68) of human primary breast cancer samples. NKD2 methylation was significantly associated with reduction of NKD2 expression, and tumor stage (p < 0.05). NKD2 suppressed breast cancer cell proliferation both in vitro and in vivo. NKD2 induced G1/S arrest and inhibited Wnt signaling in breast cancer cells. In conclusion, NKD2 is frequently methylated in human breast cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses breast cancer proliferation by inhibiting Wnt signaling.
Highlights
Breast cancer is the most common malignancy in women worldwide, and it is the second leading cause of cancer-related death among women [1]
The above results demonstrate that loss or reduction of naked cuticle homolog 1 (NKD1) and Naked cuticle homolog 2 (NKD2) expression is correlated with promoter region hypermethylation in human breast cancer cells
To determine whether NKD1 and NKD2 expression were directly regulated by promoter region methylation, MCF7, ZR75–1, MDA-MB-468, MDA-MB-231, BT474 and T47D cells were treated with the demethylating agent 5-aza-2′-deoxycytidine (5-AZA)
Summary
Breast cancer is the most common malignancy in women worldwide, and it is the second leading cause of cancer-related death among women [1]. The geographical variation indicates that environmental factors may play a significant role in the risk of breast cancer development. Epigenetic changes are strongly influenced by environmental factors. Aberrant epigenetic changes have been frequently reported in human breast cancer [3]. Wnt signaling has been reported to play important roles in mammary gland development and breast tumorigenesis [4]. Genetic mutations in APC and CTNNB1 (β-catenin encoding gene) are major contributors to colorectal carcinogenesis. Genetic mutations in these genes are not key contributors to breast cancer development [5, 6]. It has been demonstrated that only 6% of breast cancers harbor mutations in the APC gene, and no mutations in CTNNB1 have been identified in breast cancer [7, 8]. Epigenetics may play an important role in breast cancer development
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