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

• Published in: Oncogene 2020-10, Vol.39 (41), p.6421-6436
• Main Authors: Murray, Andrew S., Hyland, Thomas E., Sala-Hamrick, Kimberley E., Mackinder, Jacob R., Martin, Carly E., Tanabe, Lauren M., Varela, Fausto A., List, Karin
• Format: Article
• Language: English
• Subjects: 13; 13/105; 13/51; 13/89; 631/67/1347; 631/80/474; 64; 64/60; 82; 82/51; 82/80; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Breast - pathology; Breast cancer; Cancer; Carcinoma, Ductal, Breast - drug therapy; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - pathology; Cell Biology; Cell culture; Cell Line, Tumor; Cell surface; Cell Survival - genetics; Chemotherapy; Datasets as Topic; Development and progression; Disease Progression; Drug Resistance, Neoplasm - genetics; Drug therapy; Endocrine therapy; Extracellular matrix; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genetic aspects; Growth rate; Health aspects; Human Genetics; Humans; Immunoprecipitation; Internal Medicine; Invasiveness; Mammary Glands, Animal - pathology; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Methods; Mice; Mice, Knockout; Oncology; Patient outcomes; Proenzymes; Proteases; Serine; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Serine proteinase; siRNA; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor cell lines; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01436-3

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.