The long term of our studies is to understand the functional contribution of proteolytic systems to cancer progression. We have focused on the action of membrane type- matrix metalloproteinases (MT-MMPs) known to promote pro-invasive activity through tissue barriers, particularly MT1-MMP (MMP14). We now show a novel interaction between three members of the MT-MMP family, MT1- (MMP14), MT2- (MMP15), and MT3- (MP16) MP (refered here to as MT-MMPs), and the discoidin domain receptors (DDRs), a unique set of receptor tyrosine kinases (RTKs) that are specifically activated in response to collagen, which together with MT-MMPs'collagenolytic activity may orchestrate the proteolytic and adhesive programs during tumor cell dissemination. Preliminary data show a unique functional and specific relationship between MT-MMPs and DDRs that leads to downregulation of collagen-evoked DDR (DDR1 and DDR2) activation in a process that goes beyond receptor cleavage. Indeed, MT-MMPs selectively cleave DDR1 but not DDR2. We also report a gradual loss of DDR1 expression in invasive breast carcinomas suggesting a role for DDR1 in the transition from in situ to invasive carcinoma. Since DDR1 has been implicated in maintenance of normal mammary epithelial function and DDR2 may be associated with mesenchymal- like phenotypes, we posit that a differential regulation of DDRs by MT-MMPs may contribute to the disruption of normal breast tissue architecture and function that leads to malignant cancer. To test this hypothesis we propose thre Specific Aims: 1) To investigate the structural bases, molecular mechanisms, and functional consequences of DDR/MT-MMP interactions, 2) To investigate the expression of DDRs and MT1-MMP in human breast cancer tissues, and 3) To Investigate the DDR/MT1-MMP interplay in experimental models of breast epithelial-matrix interactions. The studies in this application will fill a wide gap of knowledge on our understanding of DDR regulation and function, and wil shed light on how their interactions with MT-MMPs influence cell behavior in normal and malignant breast epithelium. We hope that this new knowledge will help to develop better therapeutic and diagnostic strategies to improve survival in breast cancer patients.

Public Health Relevance

The development of tumor metastasis continues to be the major limitation in our ability to control cancer and improve survival. Metastasis depends on specific interactions between the cancer cells and the tissue barriers they have to invade during dissemination. We have identified a unique interaction between enzymes that degrades tissue barriers and a group of receptors that serves cells to attach. These receptors belong to the family of receptor kinases that are potential therapeutic targets in cancer. Our studies unveiled a novel functional relationship between the tissue-breaking enzymes and the kinase receptor that may regulate the migratory and invasive activities of cancer cells. The studies of this application will focus on understanding this relationship in normal and malignant breast cancer cells and in breast cancer tissues of human patients. We expect that the information gathered from this application will contribute to the diagnosis of breast cancer and to the design of new therapies aimed at controlling cancer dissemination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061986-19
Application #
8657985
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Snyderwine, Elizabeth G
Project Start
1995-07-06
Project End
2016-04-30
Budget Start
2014-05-06
Budget End
2015-04-30
Support Year
19
Fiscal Year
2014
Total Cost
$252,540
Indirect Cost
$86,395
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Fu, Hsueh-Liang; Valiathan, Rajeshwari R; Payne, Leo et al. (2014) Glycosylation at Asn211 regulates the activation state of the discoidin domain receptor 1 (DDR1). J Biol Chem 289:9275-87
Fu, Hsueh-Liang; Sohail, Anjum; Valiathan, Rajeshwari R et al. (2013) Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases. J Biol Chem 288:12114-29
Fu, Hsueh-Liang; Valiathan, Rajeshwari R; Arkwright, Richard et al. (2013) Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling. J Biol Chem 288:7430-7
Valiathan, Rajeshwari R; Marco, Marta; Leitinger, Birgit et al. (2012) Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev 31:295-321
Sohail, Anjum; Marco, Marta; Zhao, Huiren et al. (2011) Characterization of the dimerization interface of membrane type 4 (MT4)-matrix metalloproteinase. J Biol Chem 286:33178-89
Sabbota, Aaron L; Kim, Hyeong-Reh Choi; Zhe, Xiaoning et al. (2010) Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration. Cancer Res 70:5558-66
Fortin, Carl F; Sohail, Anjum; Sun, Qing et al. (2010) MT6-MMP is present in lipid rafts and faces inward in living human PMNs but translocates to the cell surface during neutrophil apoptosis. Int Immunol 22:637-49
Kim, Seaho; Huang, Wei; Mottillo, Emilio P et al. (2010) Posttranslational regulation of membrane type 1-matrix metalloproteinase (MT1-MMP) in mouse PTEN null prostate cancer cells: Enhanced surface expression and differential O-glycosylation of MT1-MMP. Biochim Biophys Acta 1803:1287-97
Lee, Mijoon; Celenza, Giuseppe; Boggess, Bill et al. (2009) A potent gelatinase inhibitor with anti-tumor-invasive activity and its metabolic disposition. Chem Biol Drug Des 73:189-202
Cho, Jin-Ah; Osenkowski, Pamela; Zhao, Huiren et al. (2008) The inactive 44-kDa processed form of membrane type 1 matrix metalloproteinase (MT1-MMP) enhances proteolytic activity via regulation of endocytosis of active MT1-MMP. J Biol Chem 283:17391-405

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