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The cell-surface anchored serine protease TMPRSS13 promotes breast cancer progression and resistance to chemotherapy

Oncogene volume 39, pages 6421–6436 (2020)Cite this article

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Abstract

Breast cancer progression is accompanied by increased expression of extracellular and cell-surface proteases capable of degrading the extracellular matrix as well as cleaving and activating downstream targets. The type II transmembrane serine proteases (TTSPs) are a family of cell-surface proteases that play critical roles in numerous types of cancers. Therefore, the aim of this study was to identify novel and uncharacterized TTSPs with differential expression in breast cancer and to determine their potential roles in progression. Systematic in silico data analysis followed by immunohistochemical validation identified increased expression of the TTSP family member, TMPRSS13 (transmembrane protease, serine 13), in invasive ductal carcinoma patient tissue samples compared to normal breast tissue. To test whether loss of TMPRSS13 impacts tumor progression, TMPRSS13 was genetically ablated in the oncogene-induced transgenic MMTV-PymT tumor model. TMPRSS13 deficiency resulted in a significant decrease in overall tumor burden and growth rate, as well as a delayed formation of detectable mammary tumors, thus suggesting a causal relationship between TMPRSS13 expression and the progression of breast cancer. Complementary studies using human breast cancer cell culture models revealed that siRNA-mediated silencing of TMPRSS13 expression decreases proliferation, induces apoptosis, and attenuates invasion. Importantly, targeting TMPRSS13 expression renders aggressive triple-negative breast cancer cell lines highly responsive to chemotherapy. At the molecular level, knockdown of TMPRSS13 in breast cancer cells led to increased protein levels of the tumor-suppressive protease prostasin. TMPRSS13/prostasin co-immunoprecipitation and prostasin zymogen activation experiments identified prostasin as a potential novel target for TMPRSS13. Regulation of prostasin levels may be a mechanism that contributes to the pro-oncogenic properties of TMPRSS13 in breast cancer. TMPRSS13 represents a novel candidate for targeted therapy in combination with standard of care chemotherapy agents in patients with hormone receptor-negative breast cancer or in patients with tumors refractory to endocrine therapy.

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Fig. 1: TMPRSS13 expression in breast cancer.
Fig. 2: TMPRSS13 protein expression is elevated in IDC.
Fig. 3: Delayed tumor development, smaller tumors, and decreased lung metastasis in TMPRSS13−/− mice.
Fig. 4: Decreased proliferation and increased apoptosis in TMPRSS13-deficient mammary tumors.
Fig. 5: TMPRSS13 silencing in human breast cancer cells decreases proliferation, increases apoptosis, and impairs invasion.
Fig. 6: TMPRSS13 silencing leads to increased protein levels of the tumor suppressor protease prostasin.
Fig. 7: TMPRSS13 levels are increased in TNBC patients and increased chemosensitivity is observed upon TMPRSS13 silencing in TNBC cell lines.

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Acknowledgements

This work was supported by NIH/NCI R01CA160565 grant (KL), NIH/NCI R01CA160565-04S grant (KL, FAV), NIH/NCI R01CA222359 (KL), NIH/NCI F31CA217148 (FAV), NIGMS/NIH grant R25 GM 058905-15 (FAV), NIH Ruth L. Kirschstein National Research Service Award T32-CA009531 (ASM and CEM) and The DeRoy Testamentary Foundation (ASM).

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  1. Department of Pharmacology, Wayne State University, Detroit, MI, USA

    Andrew S. Murray, Thomas E. Hyland, Kimberley E. Sala-Hamrick, Jacob R. Mackinder, Carly E. Martin, Lauren M. Tanabe, Fausto A. Varela & Karin List

  2. Department of Oncology, Wayne State University, Detroit, MI, USA

    Andrew S. Murray, Carly E. Martin & Karin List

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Murray, A.S., Hyland, T.E., Sala-Hamrick, K.E. et al. The cell-surface anchored serine protease TMPRSS13 promotes breast cancer progression and resistance to chemotherapy. Oncogene 39, 6421–6436 (2020). https://doi.org/10.1038/s41388-020-01436-3

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