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Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109

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Abstract

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.

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Acknowledgments

This work was supported by United States Department of Defense Breast Cancer Research Program concept grant W81XWH-06-1-0605 (ESR), Florida Department of Health Bankhead-Coley New Investigator Research Grant 07BN-07 (ESR), and the National Cancer Institute CA122086 (DCR)

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  1. Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Alexandra Hockla, Derek C. Radisky & Evette S. Radisky

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  1. Alexandra Hockla
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Correspondence to Evette S. Radisky.

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Supplemental Fig. 1

Transcriptional upregulation of selected serine proteases in T4-2 cells as compared with S1 cells. Quantitative PCR was used to assess transcript levels of mesotrypsin, prostatin, TMPRSS3, neurotrypsin, and matriptase-1 in cDNA isolated from S1 and T4-2 cells grown in 3D. Data are expressed as mean ± SD. P < 0.05 (unpaired t test) for all comparisons. (PDF 29 kb)

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Hockla, A., Radisky, D.C. & Radisky, E.S. Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109. Breast Cancer Res Treat 124, 27–38 (2010). https://doi.org/10.1007/s10549-009-0699-0

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