S. Villwock (Aachen, Germany)
Universitätsklinikum AachenAuthor Of 1 Presentation
108P - Epigenetic regulation of the putative breast cancer metastasis suppressor gene SCN4B
Abstract
Background
Breast cancer is still the leading cause of cancer deaths in women worldwide. While SCN4B is considered to be a novel metastasis suppressor gene in breast cancer, very little is known about its epigenetic regulation – in particular its downregulation in cancer tissue. In this study we explored SCN4B epigenetic regulation by promotor methylation and histone deacetylation and the clinical properties of breast tumors showing loss of SCN4B.
Methods
After performing methylation analysis of the SCN4B promotor region with data obtained from the TCGA data base, SCN4B methylation and expression levels were investigated in breast cancer cell lines by pyrosequencing and qPCR, respectively. Next, cell lines were treated with methyltransferase inhibitor 5-azacytidine (AZA) and histone deacetylase inhibitor trichostatin A (TSA) to investigate possible re-expression of SCN4B. To study clinical properties, a tissue micro array (TMA) containing 420 breast cancer samples (Bavarian breast cancer cohort) was stained with a SCN4B antibody and evaluated using IRS classification.
Results
TCGA data clearly showed higher SCN4B methylation levels in breast cancer tissues compared to normal tissue (p < 0.001) as well as lower SCN4B mRNA expression (p < 0.001) in cancer – with moderate correlation between the two. Concordantly, breast cancer cell lines showed high promotor methylation levels. After AZA and TSA treatment, cell lines exhibited increased SCN4B mRNA expression up to 200-fold. TMA staining showed significantly longer metastasis- and local recurrence-free survival for tumors retaining SCN4B protein expression, as well as correlations between SCN4B protein expression and several clinicopathological parameters such as molecular subtype where loss of SCN4B was particularly substantial in triple negative breast cancer (TNBC). Interestingly, Ki67 was inversely correlated (p < 0.01) with SCN4B expression.
Conclusions
Our findings indicate that SCN4B is a novel metastasis suppressor gene that is epigenetically downregulated in breast cancer, especially in TNBC. Interfering with the cellular signaling pathways normally suppressed by SCN4B may open new avenues to treat triple negative breast cancer.
Legal entity responsible for the study
The authors.
Funding
European Union (Horizon 2020).
Disclosure
All authors have declared no conflicts of interest.