Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation

Abstract

We have shown that prostasin serine protease is downregulated in high-grade prostate tumors and inhibits invasiveness of prostate cancer cell lines upon enforced reexpression. In our study, prostasin mRNA and protein were shown to be expressed in normal human mammary epithelial cells (NHMEC), the poorly invasive breast carcinoma cell line MCF-7 and the nonmetastatic breast carcinoma cell line MDA-MB-453, but absent in highly invasive and metastatic breast carcinoma cell lines MDA-MB-231 and MDA-MB-435s. Enforced reexpression of prostasin in MDA-MB-231 and MDA-MB-435s reduced the in vitro invasiveness of either cell line by 50%. Examination of the prostasin gene promoter and first exon revealed a GC-enriched region that contains transcription regulatory elements. The promoter and exon 1 region of the prostasin gene was investigated for DNA methylation in NHMEC and the carcinoma cell lines. The results revealed a methylation pattern that correlates with prostasin expression in these cells. Demethylation coupled with histone deacetylase inhibition resulted in reactivated expression of the prostasin mRNA in MDA-MB-231 and MDA-MB-435s cells. These results suggest that prostasin expression in breast cancer cells may be regulated by DNA methylation and that an absence of prostasin expression may contribute to breast cancer invasiveness and metastatic potential.