1. The SHISA3 gene was found to be silenced through promoter methylation at higher levels in breast cancer tissues compared to normal breast tissues.
Evidence Rating Level: 1 (Excellent)
Breast cancer (BC) accounts for 15% of tumor related deaths in women, translating to over 627,000 deaths worldwide in 2018 alone. Late diagnosis is considered to be a primary reason for high BC mortality rates, which can be attributed to a scarcity of reliable biomarkers for early stage diagnosis. On the molecular scale, the Wnt signalling pathway plays a role in mammary gland development, with Wnt proteins controlling the growth of ducts in mammary tissue. As well, abnormal activation of this pathway has been correlated to BC development, and so has stabilization of β-Catenin, a regulator of this pathway. SHISA3 is a potential tumour suppressor gene, with the SHISA3 protein acting as an antagonist to Wnt/β-catenin signalling. Epigenetic inactivation of SHISA3 has been found in laryngeal squamous cell and nasopharyngeal carcinoma, though it has not been thoroughly investigated in BC. The current study aimed to investigate SHISA3 gene expression levels in BC cell lines and tissues, as a reduction in SHISA3 expression may provide a biological mechanism for BC development. Three BC cell lines, as well as BC and normal breast tissue samples from 103 patients, were examined in this study. The results found that mRNA levels of SHISA3 were significantly lower in BC tissues than normal breast tissues, as much as 22 times lower in the invasive ductal carcinoma subtype. Additionally, the promoter of SHISA3 was found to be methylated at higher rates in BC tissues than normal tissues (61% vs 18% of samples respectively). Methylation of the promoter was experimentally found to effectively silence the SHISA3 gene. Furthermore, ectopic expression of SHISA3 was shown to substantially reduce the migration ability and proliferative potential of these cells. Study findings appear to identify SHISA3 as a tumour suppressor gene that may have powerful therapeutic implications in BC.
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