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Serine protease PRSS23 is upregulated by estrogen receptor ? and associated with proliferation of breast cancer cells.

ABSTRACT: Serine protease PRSS23 is a newly discovered protein that has been associated with tumor progression in various types of cancers. Interestingly, PRSS23 is coexpressed with estrogen receptor ? (ER?), which is a prominent biomarker and therapeutic target for human breast cancer. Estrogen signaling through ER? is also known to affect cell proliferation, apoptosis, and survival, which promotes tumorigenesis by regulating the production of numerous downstream effector proteins.In the present study, we aimed to clarify the correlation between and functional implication of ER? and PRSS23 in breast cancer. Analysis of published breast cancer microarray datasets revealed that the gene expression correlation between ER? and PRSS23 is highly significant among all ER?-associated proteases in breast cancer. We then assessed PRSS23 expression in 56 primary breast cancer biopsies and 8 cancer cell lines. The results further confirmed the coexpression of PRSS23 and ER? and provided clinicopathological significance. In vitro assays in MCF-7 breast cancer cells demonstrated that PRSS23 expression is induced by 17?-estradiol-activated ER? through an interaction with an upstream promoter region of PRSS23 gene. In addition, PRSS23 knockdown may suppress estrogen-driven cell proliferation of MCF-7 cells.Our findings imply that PRSS23 might be a critical component of estrogen-mediated cell proliferation of ER?-positive breast cancer cells. In conclusion, the present study highlights the potential for PRSS23 to be a novel therapeutic target in breast cancer research.

SUBMITTER: Chan HS

PROVIDER: S-EPMC3264607 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Serine protease PRSS23 is upregulated by estrogen receptor α and associated with proliferation of breast cancer cells.

Chan Hau-Shien HS Chang Shing-Jyh SJ Wang Tao-Yeuan TY Ko Hung-Ju HJ Lin Yu-Chih YC Lin Kuan-Ting KT Chang Kuo-Ming KM Chuang Yung-Jen YJ

PloS one 20120123 1

Serine protease PRSS23 is a newly discovered protein that has been associated with tumor progression in various types of cancers. Interestingly, PRSS23 is coexpressed with estrogen receptor α (ERα), which is a prominent biomarker and therapeutic target for human breast cancer. Estrogen signaling through ERα is also known to affect cell proliferation, apoptosis, and survival, which promotes tumorigenesis by regulating the production of numerous downstream effector proteins.In the present study, w ...[more]

PMID: 22291950

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Project description:HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p?=?0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR?=?0.45 [CI 0.23-0.90], p?=?0.023; HR?=?0.55 [CI 0.32-0.94], p?=?0.028, respectively), with even more pronounced impact in node-positive patients (HR?=?0.21 [CI 0.07-0.63], p?=?0.006; HR?=?0.29 [CI 0.13-0.65], p?=?0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n?=?2809): HR?=?0.79 [CI 0.7-0.9], log-rank p?=?0.0003; for OS (n?=?971): HR?=?0.63 [CI 0.48-0.83], log-rank p?=?0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.

Dataset Information

Serine protease PRSS23 is upregulated by estrogen receptor ? and associated with proliferation of breast cancer cells.

Publications

Serine protease PRSS23 is upregulated by estrogen receptor α and associated with proliferation of breast cancer cells.

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