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Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) are a broadly expressed family of matrisome proteins that are the primary regulators of matrix metalloproteinases (MMPs). In addition to their originally described function, TIMPs display a broad range of MMP independent biological functions associated with proliferation, apoptosis, migration, and differentiation. MMPs are zinc containing endopeptidases that play an essential role in maintaining the extracellular matrix (ECM) through proteolytic turnover; a balancing act maintained (in part) by the local MMP:TIMP ratio. Disturbances in the balance between MMPs and TIMPs is associated with various disease states, including cancer, heart disease, arthritis, and cognitive dysfunction. While TIMPs are classically characterized as regulators of MMP proteolytic activity, we describe a novel mode of MMP-dependent regulation of TIMP function. We show that active MMP9 (aMMP9) in molar excess can cleave TIMP proteins within their C-terminal domains. As a result of this cleavage, the MMP-dependent and MMP-independent functions of the TIMP proteins are predicted to be altered. MMP9 has been found to contribute to the pathogenesis of many cancer types including breast cancer. Additionally, MMP9 is described as a breast cancer biomarker, with high levels of MMP9 being associated with a worse prognosis. Previous research from our lab has shown recombinant TIMP2 may represent a novel biological therapeutic in triple negative breast cancer models. Utilizing murine models of breast cancer, we describe the prevalence of TIMP cleavage in 4T1 breast tumors as well as the functional outcomes of TIMP cleavage within this model system. Studying the outcomes of TIMP regulation by MMPs may allow researchers to target this model system more effectively in translational studies of breast cancer. Citation Format: Sasha Coates-Park, Sadeechya Gurung, Josh Rich, William Stetler-Stevenson, David Peeney. Regulation of TIMPs through MMP dependent cleavage in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2354. |
