Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109.
Serine proteases have been implicated in many stages of cancer development, facilitating tumor cell growth, invasion, and metastasis, and naturally occurring serine protease inhibitors have shown promise as potential anticancer therapeutics. Optimal design of inhibitors as potential therapeutics requires the identification of the specific serine proteases involved in disease progression and the functional targets responsible for the tumor-promoting properties. Here, we use the HMT-3522 breast cancer progression series grown in 3D organotypic culture conditions to find that serine protease inhibitors cause morphological reversion of the malignant T4-2 cells, assessed by inhibition of proliferation and formation of acinar structures with polarization of basal markers, implicating serine protease activity in their malignant growth behavior. We identify PRSS3/mesotrypsin upregulation in T4-2 cells as compared to their nonmalignant progenitors, and show that knockdown of PRSS3 attenuates, and treatment with recombinant purified mesotrypsin enhances, the malignant growth phenotype. Using proteomic methods, we identify CD109 as the functional proteolytic target of mesotrypsin. Our study identifies a new mediator and effector of breast cancer growth and progression.
Hockla
Alexandra
A
Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Radisky
Derek C
DC
Radisky
Evette S
ES
D015703:Antigens, CD / Q000378:metabolism*; D007611:Aprotinin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D016764:Cell Polarity; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic; D014357:Trypsin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; C120523:CD109 protein, human; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D007611:Aprotinin; C040749:PRSS3 protein, human; D014357:Trypsin