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 #
5R01CA061986-17
Application #
8293054
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Snyderwine, Elizabeth G
Project Start
1995-07-06
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
17
Fiscal Year
2012
Total Cost
$260,352
Indirect Cost
$89,068
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Koh, Minsoo; Woo, Yunjung; Valiathan, Rajeshwari R et al. (2015) Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition. Int J Cancer 136:E508-20
Toy, Kathy A; Valiathan, Rajeshwari R; Núñez, Fernando et al. (2015) Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat 150:9-18
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; 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
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
Toth, Marta; Sohail, Anjum; Fridman, Rafael (2012) Assessment of gelatinases (MMP-2 and MMP-9) by gelatin zymography. Methods Mol Biol 878:121-35
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
Nuti, Elisa; Casalini, Francesca; Santamaria, Salvatore et al. (2011) Synthesis and biological evaluation in U87MG glioma cells of (ethynylthiophene)sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors. Eur J Med Chem 46:2617-29
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

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