Mechanisms of Deregulation of Matriptase in Breast Cancer

Summary

Principal Investigator: Chen Yong Lin
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2010-04-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Regulation of the matriptase-prostasin cell surface proteolytic cascade by hepatocyte growth factor activator inhibitor-1 during epidermal differentiation
    Ya Wen Chen
    Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201, USA
    J Biol Chem 285:31755-62. 2010
  2. pmc Human cancer cells retain modest levels of enzymatically active matriptase only in extracellular milieu following induction of zymogen activation
    Li Ling Chu
    Department of Pharmacy, Chi Mei Medical Center, Tainan, Taiwan
    PLoS ONE 9:e92244. 2014
  3. pmc Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas
    Feng Pai Chou
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
    Am J Pathol 183:1306-17. 2013
  4. pmc Matriptase expression and zymogen activation in human pilosebaceous unit
    Bai Yao Wu
    Department of Dermatology, BYW, National Defense Medical Center, Taipei, Taiwan, ROC
    J Histochem Cytochem 62:50-9. 2014
  5. pmc Matriptase regulates proliferation and early, but not terminal, differentiation of human keratinocytes
    Ya Wen Chen
    1 Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, USA 2 Graduate Program in Life Science, University of Maryland, Baltimore, Maryland, USA
    J Invest Dermatol 134:405-14. 2014
  6. pmc Antithrombin regulates matriptase activity involved in plasmin generation, syndecan shedding, and HGF activation in keratinocytes
    Ya Wen Chen
    Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, United States of America
    PLoS ONE 8:e62826. 2013
  7. pmc Mechanisms for the control of matriptase activity in the absence of sufficient HAI-1
    Han Xu
    Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD 21201, USA
    Am J Physiol Cell Physiol 302:C453-62. 2012
  8. pmc Targeting zymogen activation to control the matriptase-prostasin proteolytic cascade
    Zhenghong Xu
    School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA
    J Med Chem 54:7567-78. 2011
  9. pmc Matriptase is inhibited by extravascular antithrombin in epithelial cells but not in most carcinoma cells
    Feng Pai Chou
    Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA
    Am J Physiol Cell Physiol 301:C1093-103. 2011
  10. pmc Transport via the transcytotic pathway makes prostasin available as a substrate for matriptase
    Stine Friis
    Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
    J Biol Chem 286:5793-802. 2011

Research Grants

Detail Information

Publications13

  1. pmc Regulation of the matriptase-prostasin cell surface proteolytic cascade by hepatocyte growth factor activator inhibitor-1 during epidermal differentiation
    Ya Wen Chen
    Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201, USA
    J Biol Chem 285:31755-62. 2010
    ....
  2. pmc Human cancer cells retain modest levels of enzymatically active matriptase only in extracellular milieu following induction of zymogen activation
    Li Ling Chu
    Department of Pharmacy, Chi Mei Medical Center, Tainan, Taiwan
    PLoS ONE 9:e92244. 2014
    ..Our study suggests that cellular free, active matriptase is scarce and might not be an effective target for in vivo imaging and drug development. ..
  3. pmc Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas
    Feng Pai Chou
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
    Am J Pathol 183:1306-17. 2013
    ....
  4. pmc Matriptase expression and zymogen activation in human pilosebaceous unit
    Bai Yao Wu
    Department of Dermatology, BYW, National Defense Medical Center, Taipei, Taiwan, ROC
    J Histochem Cytochem 62:50-9. 2014
    ..Our observations suggest that the matriptase-HGF-c-MET pathway has the potential to be engaged, primarily in proliferative cells rather than terminally differentiated epithelial cells of the human pilosebaceous unit. ..
  5. pmc Matriptase regulates proliferation and early, but not terminal, differentiation of human keratinocytes
    Ya Wen Chen
    1 Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, USA 2 Graduate Program in Life Science, University of Maryland, Baltimore, Maryland, USA
    J Invest Dermatol 134:405-14. 2014
    ....
  6. pmc Antithrombin regulates matriptase activity involved in plasmin generation, syndecan shedding, and HGF activation in keratinocytes
    Ya Wen Chen
    Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, United States of America
    PLoS ONE 8:e62826. 2013
    ....
  7. pmc Mechanisms for the control of matriptase activity in the absence of sufficient HAI-1
    Han Xu
    Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD 21201, USA
    Am J Physiol Cell Physiol 302:C453-62. 2012
    ..These data suggest that matriptase activity can be rapidly inhibited by HAI-1 and other HAI-1-like protease inhibitors and "locked" in an inactive autoactivation intermediate, all of which places matriptase under very tight control...
  8. pmc Targeting zymogen activation to control the matriptase-prostasin proteolytic cascade
    Zhenghong Xu
    School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA
    J Med Chem 54:7567-78. 2011
    ..Our results suggest that inhibiting matriptase activation is an efficient way to control matriptase function...
  9. pmc Matriptase is inhibited by extravascular antithrombin in epithelial cells but not in most carcinoma cells
    Feng Pai Chou
    Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA
    Am J Physiol Cell Physiol 301:C1093-103. 2011
    ..Taken together these data suggest that normal epithelial cells employ a dual mechanism involving HAI-1 and antithrombin to control matriptase and that the antithrombin-based mechanism appears lost in the majority of carcinoma cells...
  10. pmc Transport via the transcytotic pathway makes prostasin available as a substrate for matriptase
    Stine Friis
    Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
    J Biol Chem 286:5793-802. 2011
    ..This study suggests a possible explanation for how matriptase or other basolateral serine proteases activate prostasin on its way to its apical destination...
  11. pmc Increased matriptase zymogen activation in inflammatory skin disorders
    Cheng jueng Chen
    Dept of Dermatolog, Tri Service General Hospital, Taipei, Taiwan, R O C
    Am J Physiol Cell Physiol 300:C406-15. 2011
    ..These findings suggest that inflammation-associated reactive oxygen species and tissue acidity may enhance matriptase activation in some skin diseases...
  12. pmc Matriptase autoactivation is tightly regulated by the cellular chemical environments
    Jehng Kang Wang
    Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
    PLoS ONE 9:e93899. 2014
    ..Our results suggest that matriptase can act as a cellular sensor of the chemical environment of the cell that allows the cell to respond to and protect itself from changes in the chemical milieu. ..

Research Grants30

  1. Proteolytic matriptase-prostasin axis in breast cancer
    Karin List; Fiscal Year: 2013
    ..The combination of state-of-the art mouse genetics with 2D and 3D cell culture based assays encompasses an innovative strategy for studying human cancerous disease, and may offer new avenues for diagnosis and therapy of breast cancer. ..