Matriptase is a serine protease that is expressed in the epithelial components of essentially all epithelial tissues including the mammary gland. We have shown that in these tissues, Hepatocyte Growth factor Activator Inhibitor-1 (HAI-1), a kunitz-type protease inhibitor, is required for the normal regulation of matriptase expression and activation, and is responsible for inhibiting the enzyme after it becomes activated. We and others have shown that overexpression of matriptase is a marker of poor prognosis in a variety of human cancers, including breast cancer. When overexpressed in the skin of transgenic mice, matriptase has been shown to act as an oncogene - an effect blocked by HAI-1 overexpression. Several substrates activated by matriptase are believed to be involved in carcinogenesis and/or tumor progression, such as Hepatocyte Growth Factor, or Urokinase Plasminogen Activator, however, much remains to be discovered about the role of misregulated matriptase activity in cancer, and the underlying biochemical mechanisms involved. To explore the role of the matriptase/HAI-1 system in the mammary gland we have developed two transgenic mouse models in which we can induce the overexpression of HAI-1 or matriptase in mammary epithelial tissue. Using these models we have shown that altering the matriptase/HAI-1 balance can have a profound effect on mammary gland biology, function, and carcinogenesis. These findings are consistent with our previously published studies analyzing human tumor samples which demonstrated that overexpression of matriptase is associated with poor prognosis in node-negative breast cancer. This proposal will bridge the gap between these two bodies of work by developing an integrated understanding of the role of the matriptase/HAI-1 system in mammary gland biology, carcinogenesis and tumor progression, the biochemical mechanisms involved in these processes, and the clinical implications of their disruption in breast cancer.
In Aim 1 we will use our transgenic systems to study the regulation of normal mammary gland biology, mammary carcinogenesis, and metastatic tumor behavior, by the matriptase/HAI-1 system, and will study the underlying mechanisms involved.
In Aim 2 we will examine the role of hypoxia and aberrant glycosylation in the aberrant regulation of matriptase activity.
In aim 3 we evaluate the clinical importance of our data by integrating the findings of the previous two aims with an analysis of primary human breast tumor samples. We will evaluate the utility of matriptase and HAI-1, alone or in combination with markers of hypoxia or altered glycosylation, as prognostic markers of clinical outcome in breast cancer. We believe that these studies will highlight the importance of the matriptase/HAI-1 system in breast cancer and will provide valuable insights as to how the pathway might be targeted therapeutically.

Public Health Relevance

Overexpression of the serine protease matriptase has been shown to be a marker of poor prognosis in several types of cancer including breast cancer, and in an animal model has been shown to act as an oncogene. Although matriptase is known to activate several proteins thought to play a role in carcinogenesis and tumor progression, much remains to be discovered about the role of this protease in carcinogenesis and the normal development and function of epithelial tissues. This proposal will make use of novel in vivo and in vitro models combined with analysis of clinical materials, to develop an integrated understanding of the role of the matriptase/HAI-1 system in normal mammary gland development, function, carcinogenesis and tumor progression, and will evaluate the utility of matriptase and HAI-1 as markers of breast cancer prognosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123223-03
Application #
8212512
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$312,409
Indirect Cost
$68,021
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Lai, Chih-Hsin; Lai, Ying-Jung J; Chou, Feng-Pai et al. (2016) Matriptase Complexes and Prostasin Complexes with HAI-1 and HAI-2 in Human Milk: Significant Proteolysis in Lactation. PLoS One 11:e0152904
Lai, Chih-Hsin; Chang, Shun-Cheng; Chen, Yen-Ju et al. (2016) Matriptase and prostasin are expressed in human skin in an inverse trend over the course of differentiation and are targeted to different regions of the plasma membrane. Biol Open 5:1380-1387
Chen, Ya-Wen; Yin, Shi; Lai, Ying-Jung J et al. (2016) Plasminogen-Dependent Matriptase Activation Accelerates Plasmin Generation by Differentiating Primary Human Keratinocytes. J Invest Dermatol 136:1210-8
Chen, Chi-Yung; Chen, Cheng-Jueng; Lai, Chih-Hsin et al. (2016) Increased matriptase zymogen activation by UV irradiation protects keratinocyte from cell death. J Dermatol Sci 83:34-44
Zoratti, Gina L; Tanabe, Lauren M; Hyland, Thomas E et al. (2016) Matriptase regulates c-Met mediated proliferation and invasion in inflammatory breast cancer. Oncotarget :
Lai, Ying-Jung J; Chang, Hsiang-Hua D; Lai, Hongyu et al. (2015) N-Glycan Branching Affects the Subcellular Distribution of and Inhibition of Matriptase by HAI-2/Placental Bikunin. PLoS One 10:e0132163
Chang, Hsiang-Hua D; Xu, Yuan; Lai, Hongyu et al. (2015) Differential subcellular localization renders HAI-2 a matriptase inhibitor in breast cancer cells but not in mammary epithelial cells. PLoS One 10:e0120489
Kawaguchi, Makiko; Kanemaru, Ai; Sawaguchi, Akira et al. (2015) Hepatocyte growth factor activator inhibitor type 1 maintains the assembly of keratin into desmosomes in keratinocytes by regulating protease-activated receptor 2-dependent p38 signaling. Am J Pathol 185:1610-23
Ren, Zhen-Hu; Xu, Jian-Lin; Fan, Teng-Fei et al. (2015) The Harmonic Scalpel versus Conventional Hemostasis for Neck Dissection: A Meta-Analysis of the Randomized Controlled Trials. PLoS One 10:e0132476
Wang, Jehng-Kang; Teng, I-Jou; Lo, Ting-Jen et al. (2014) Matriptase autoactivation is tightly regulated by the cellular chemical environments. PLoS One 9:e93899

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