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) Prostasin, a prostate-abundant serine protease originally discovered in human seminal fluid, 1 has recently been shown to be downregulated in high-grade (Gleason 4/5) prostate cancers and to have the ability of inhibiting invasion in vitro upon enforced reexpression in highly invasive human prostate cancer cells Prostasin is a glycosylphosphatidylinositol (GPI)-anchored active serine protease expressed in normal prostate epithelial cells and can also be secreted into the prostatic fluid. 3 The membrane-anchored but not the secreted prostasin confers the invasion suppression of prostate cancer cells. 2 Enforced reexpression of prostasin in DU-145 and PC-3 cells did not have any effect on cell proliferation. 2 Together with normal epithelial specific 1 (NES1), 4 prostase 5 and testisin, 6 these 4 and potentially more serine proteases form the foundation of a new paradigm of serine proteases and cancer. 2 First, these serine proteases are expressed in either normal prostate epithelia or cells (prostasin, NES1 and prostase), 2,4,5 normal breast epithelial cells (NES1) 4 or the pachytene spermatocytes in normal testis (testisin). 6 But they are absent or expression level-reduced in tumors or tumor cell lines of these tissues. 2,4 -6 Second, NES1 and testisin have been shown to be tumor suppressors 4,7 and prostasin may be a potential invasion suppressor. 2 These new roles of serine proteases in cancer are in sharp contrast to the view held of serine proteases' role in cancer by the conventional paradigm, that they are usually upregulated in cancer and promote cancer invasion and metastasis. 8 A classical example of the conventional paradigm of serine proteases' role in prostate and breast cancers is given with the urokinase-type plasminogen activator (uPA). uPA is upregulated in prostate and breast cancers and promotes tumor invasion. 9,10 In breast cancer cell lines, uPA expression was observed in the highly invasive, hormone-insensitive MDA-MB-231, but not in the poorly invasive, hormone-sensitive MCF-7, T-47D or normal human mammary epithelial cells (NHMEC). 11 uPA expression in breast cancer cells is regulated by promoter DNA methylation. 11,Prostasin's expression was mainly found in the prostate while a lesser amount was found in various tissues. 1,12 Prostasin expression in the breast, however, has not been examined. Several prostate-abundant serine proteases, for example, prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2), have been shown to be expressed in human breast cancer cell lines. 13 In our study, we have examined prostasin expression in NHMEC and a panel of human breast carcinoma cell lines, including the poorly invasive MCF-7, the nonmetastatic MDA-MB-453 and the highly invasive and metastati...

Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis

“…Thus, Testisin may be added to an emerging list of tumour suppressor genes that are silenced by DNA hypermethylation, including prostasin (Chen and Chai, 2002), E-cadherin (Melki et al, 2000;Nakayama et al, 2001), normal epithelial cell-specific 1 (NES1) (Li et al, 2001) and COX-2 (Kikuchi et al, 2002).…”

“…The NES1 serine protease gene is downregulated in breast and prostate cancers, and its expression is associated with a tumour suppressor function (Goyal et al, 1998;Luo et al, 2001). The prostasin gene is downregulated in prostate cancers and its expression functionally inhibits both prostate (Chen et al, 2001(Chen et al, , 2004 and breast cancer invasiveness (Chen and Chai, 2002). Similar to our observations on the Testisin gene, hypermethylation of both prostasin and NES1 genes has been reported as the basis for loss of expression of these genes in tumours (Li et al, 2001;Chen and Chai, 2002), and their effects on cells are not associated with reduced proliferation (Goyal et al, 1998;Chen et al, 2001).…”

Urinary prostasin in humans: relationships among prostasin, aldosterone and epithelial sodium channel activity

“…[17][18][19][20][21][22][23] However, the physiological role of this protein remains largely undetermined, although dysregulation of prostasin expression has been found in high-grade human prostate and breast cancers. 14,[24][25][26] Catalytically active prostasin was detected in urine from both men and women. 10 Although the concentration of prostasin in urine is lower than that in seminal fluid, the production of prostasin has to be very active in the kidney, considering the relatively large amount of the urine excreted in a day.…”

Prostasin Serine Protease as a Breast Cancer Invasion Marker and a Metastasis Suppressor

“…We have previously shown that membrane-anchored prostasin serine protease was an in vitro suppressor of tumor cell invasion (1)(2)(3). The expression of prostasin is down-regulated in prostate cancers (2), and invasive cancer cell lines of the human prostate and breast (1,3).…”

“…We have previously shown that membrane-anchored prostasin serine protease was an in vitro suppressor of tumor cell invasion (1-3). The expression of prostasin is down-regulated in prostate cancers (2), and invasive cancer cell lines of the human prostate and breast (1,3). For this project, we hypothesized that the down-regulation of prostasin is causal to breast cancer invasion and metastasis in vivo.…”