Matriptase is a cell-surface anchored serine protease that was first identified in human breast cancer cell lines and has subsequently been implicated in many aspects of breast cancer pathology. Matriptase is up-regulated in human breast carcinoma cancer cells, and its increased expression has been shown to correlate with poor patient outcome. Presently, it is unknown if matriptase plays a causal role in breast carcinogenesis or contributes primarily to secondary events of cancer growth and progression, and its potential as a therapeutic target remains untested. Perinatal lethality in matriptase loss-of-function mice has thus far precluded analysis of the effect of matriptase ablation in the mammary gland;however our proposal presents novel techniques to bypass this limitation. In our proposed study both functional and mechanistic characterization of matriptase's role in breast cancer will be performed using parallel and complimentary in vitro and in vivo """"""""loss-of-function"""""""" techniques. Our previous research has identified the GPI-anchored serine protease prostastin as a physiological substrate and downstream effector of matriptase proteolytic activity, and we will focus on this proteolytic axis for its potential contribution to breast cance biology. We believe there to be a significant correlation between these two proteases and cancer progression, as we have demonstrated that both matriptase and prostasin play critical roles in cell to cell adhesions in vivo, and changes in levels of either protein can perturb these adhesions via disruption of epithelial tight junction formation and integrity. The hypothesis to be tested is that matriptase exerts critical functions through activation of the prostasin zymogen and that the matriptase/prostasin proteolytic pathway is critical for breast oncogenesis, specifically through the loss of cell-cell adhesions, and thereby the promotion of carcinogenesis in vivo. To test this hypothesis, we formulated two specific aims. In the first aim the significance of the matriptase/prostasin proteolytic axis in breast cancer initiation and progression will be determined using both matriptase and prostasin loss-of-function novel genetic mouse models. In the second aim the role of prostasin in cell-cell adhesion in breast cancer will be studied with emphasis on its role in tight junction function and integrity. 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.
Extracellular proteases are the subject of intensive efforts by the pharmaceutical industry to develop new treatment strategies for human diseases, including breast cancer. We propose to study and validate a protease pathway, the matriptase-prostasin proteolytic pathway, that is active in the tumor microenvironment and that may mediate the progression from normal breast epithelium to malignant and metastatic lesions. We anticipate that our studies will identify a novel target which can be used to develop strategies to abrogate breast cancer progression.
|Murray, Andrew S; Varela, Fausto A; Hyland, Thomas E et al. (2017) Phosphorylation of the type II transmembrane serine protease, TMPRSS13, in hepatocyte growth factor activator inhibitor-1 and -2-mediated cell-surface localization. J Biol Chem 292:14867-14884|
|Tanabe, Lauren M; List, Karin (2017) The role of type II transmembrane serine protease-mediated signaling in cancer. FEBS J 284:1421-1436|
|Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2 (see original citation for additional authors) (2016) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer. Gynecol Oncol 141:386-401|
|Murray, Andrew S; Varela, Fausto A; List, Karin (2016) Type II transmembrane serine proteases as potential targets for cancer therapy. Biol Chem 397:815-26|
|Duhaime, Michael J; Page, Khaliph O; Varela, Fausto A et al. (2016) Cell Surface Human Airway Trypsin-Like Protease Is Lost During Squamous Cell Carcinogenesis. J Cell Physiol 231:1476-83|
|Zoratti, Gina L; Tanabe, Lauren M; Varela, Fausto A et al. (2015) Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling. Nat Commun 6:6776|
|Kelemen, Linda E; Lawrenson, Kate; Tyrer, Jonathan et al. (2015) Genome-wide significant risk associations for mucinous ovarian carcinoma. Nat Genet 47:888-97|
|Miller, Gregory S; Zoratti, Gina L; Murray, Andrew S et al. (2014) HATL5: a cell surface serine protease differentially expressed in epithelial cancers. PLoS One 9:e87675|
|McCann, Susan E; Edge, Stephen B; Hicks, David G et al. (2014) A pilot study comparing the effect of flaxseed, aromatase inhibitor, and the combination on breast tumor biomarkers. Nutr Cancer 66:566-75|
|Ghoussaini, Maya; Edwards, Stacey L; Michailidou, Kyriaki et al. (2014) Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun 4:4999|
Showing the most recent 10 out of 14 publications