TY - JOUR
T1 - Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109
AU - Hockla, Alexandra
AU - Radisky, Derek C.
AU - Radisky, Evette S.
N1 - Funding Information:
Acknowledgments This work was supported by United States Department of Defense Breast Cancer Research Program concept
Funding Information:
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)
PY - 2010/11
Y1 - 2010/11
N2 - 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.
AB - 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.
KW - Protease inhibitors
KW - Proteases
KW - Three-dimensional culture models
KW - Tumor microenvironment
KW - Tumor reversion
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U2 - 10.1007/s10549-009-0699-0
DO - 10.1007/s10549-009-0699-0
M3 - Article
C2 - 20035377
AN - SCOPUS:77957716350
SN - 0167-6806
VL - 124
SP - 27
EP - 38
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 1
ER -