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Role of MT1-MMP in protection of breast tumor cells against host immune attack
Tumor Cell Biology I
Background: Membrane type-1 matrix metalloproteinase (MT1-MMP) is a key player in mammary neoplasms. MT1-MMP is essential for the invasion and metastasis of malignant tumors. Accordingly, it is a promising drug target. Recently, we identified a novel and functionally important function of MT1-MMP in mammary carcinomas: MT1-MMP defends malignant cells against the host’s immune system, thus making mammary carcinomas resistant to immune attack. Activation of the complement system initiates the host’s immune response and triggers the multicomponent immune system. MT1-MMP, however, blocks complement activation thus allowing mammary carcinomas, which express MT1-MMP, to escape immune attack, to invade the tissues, and to metastasize. Hypothesis: We hypothesize that MT1-MMP plays a significant and previously unknown role in the protection of breast tumor cells from host immunity. Our results strongly suggest that MT1-MMP, through a dual mechanism, defends mammary carcinomas against the host’s immune system. We have determined that MT1-MMP cleaves the C3b and C4b complement components and protects breast cancer MCF7 cells from the complement attack. Our data also suggest that MT1-MMP specifically associates with the complement component C1q. We suspect that this interaction promotes breast tumor cell adhesion and aggregation and contributes to the metastasis and survival of tumor cells in the bloodstream. Specific Aims: 1. Determine the significance of the MT1-MMP/complement interactions in the survival, metastasis, and tumor growth of breast carcinoma cells (Months 1-12). 2. Define the significance of the MT1-MMP interaction with the complement component C1q in promoting tumor cell induced-platelet aggregation (TCIPA), tumor cell survival, metastasis, and adhesion (Months 13-24). Study design: We will address our hypothesis by using animal models of complement sufficient and complement deficient mice and human and murine mammary carcinoma cells. We will confirm the significance of C1q/MT1-MMP interactions by performing cell-based assays and by in vivo studies with human and murine breast cancer cells expressing wild type and mutant MT1-MMP unable to bind C1q. Potential Outcomes and Benefits of the Research: Identification of the precise functional role of MT1-MMP in tumor immunity will greatly aid in the fight against breast cancer. Our studies will validate the identification of MT1-MMP as the key candidate for drug targeting in mammary carcinomas.
Background: This proposal is written to describe our comprehensive and focused research program that has been designed to provide us with a thorough understanding of the hitherto incompletely understood role played by the complex enzyme, “Membrane type-1 Matrix Metalloproteinase” (MT1-MMP) in breast cancer. Our program is firmly and soundly anchored to the results of our many years of study of MT1-MMP. These results have conclusively proved that MT1-MMP is, one, a characteristic feature of mammary carcinomas, two, that it is directly involved in breast cancer tumor cell migration, invasion, and metastasis, and, three, that it is also an important part of the tumor defense mechanism which protects neoplastic cells from the host immune response. We are convinced that the knowledge we confidently expect to gain in the course of performing the proposed program will help us to control and, eventually, to eliminate breast cancer. Objectives/Hypothesis: The central hypothesis of the proposed research is that the ubiquitous enzyme MT1-MMP actually serves to disarm the human immune system and thus to protect the invading tumor cells from their recognition and elimination by the host immunity. We have already determined and understand the specific chemical and biological processes by which MT1-MMP protects breast carcinoma MCF7 cells from an attack by the human immune system. Specific Aims: We have divided our proposed research program into two elements. We will identify the physiological significance of the interactions of MT1-MMP with elements of the human immune system for the tumor cell growth and metastasis. We will then proceed to demonstrate that the MT1-MMP interactions with the specific component of the immune cascade promote tumor cell adhesion, aggregation, metastasis, and survival in the bloodstream. Study design: We will employ cell-based assays and well established mouse tumor models to confirm the role of MT1-MMP in defending breast tumor cells against host immune attack. Our work will be performed in mice with human and murine breast carcinoma cells. This experimental model resembles breast cancer in humans most closely. Potential Outcomes and Benefits of the Research: We are confident that our research efforts will provide solid confirmation that MT1-MMP protects tumors from the host’s immune system. This confirmation will serve as a firm basis for selecting MT1-MMP as the appropriate target for therapeutically treating breast cancer.