Abstract 3158: Characterization and targeting of TMPRSS13 in breast cancer
2021
Breast cancer (BCa) remains a significant public health burden in the United States (US) and globally, despite advances in screening, detection, and therapeutics. In the US alone, BCa is the most commonly diagnosed cancer and the second leading cause of cancer deaths in women. The discovery of novel, targetable biomarkers is therefore paramount to reduce the morbidity and mortality associated with BCa. Cancer progression is often accompanied by increased expression of pericellular proteases capable of degrading the extracellular matrix and cleaving pro-oncogenic signaling molecules. BCa cells use pericellular proteolysis in order to enhance their proliferation, survival, and invasiveness. TMPRSS13, a member of the type II transmembrane serine protease (TTSP) family, has emerged as a potential biomarker and therapeutic target in BCa. Prior data indicates that TMPRSS13 is significantly upregulated in invasive ductal carcinoma samples at the mRNA and protein levels compared to normal breast tissue. Furthermore, TMPRSS13-deficient mice have few phenotypic defects but in a genetic model of mammary cancer, TMPRSS13-deficient mice have a significantly reduced tumor burden as well as a reduction in lung metastases. This data indicates that TMPRSS13 may be a worthwhile target to treat BCa patients. However, selective targeting of TMPRSS13 above other TTSPs is difficult due to the homology of their catalytic domains. Therefore, any information that we can glean regarding the unique biochemical and oncogenic properties of TMPRSS13 will aid in the future development of inhibitors. Our group has found that TMPRSS13 is the only TTSP family member confirmed to be phosphorylated in its intracellular domain. This phosphorylation is critical for the trafficking and cell surface expression of the protease. Mutagenesis of individual amino acids as well as deletion constructs of the phosphorylated residues in the intracellular domain have indicated that the inability of TMPRSS13 to be phosphorylated does not affect its catalytic activity, but inhibits proper cell membrane localization. Thus, phosphorylation may be imperative for TMPRSS13 to interact with pro-oncogenic substrates in the tumor microenvironment. Furthermore, preliminary data has indicated that TMPRSS13 may be a substrate for phosphorylation by CDK5, a neuronal kinase that has recently emerged as pro-oncogenic in various cancer types. CDK5, when bound to myristoylated p35, likely phosphorylates TMPRSS13 at the cell membrane, allowing TMPRSS13 to stably localize to the cell surface of both luminal and triple negative BCa cells. The overarching goal of our project is to fully understand the manner in which TMPRSS13 promotes the development and progression of BCa, which will allow for the design of selective targeted inhibitors in the future. Citation Format: Carly E. Martin, Andrew S. Murray, Evan Harrison, Karin List. Characterization and targeting of TMPRSS13 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3158.
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