The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis
Copyright policy )The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis
A disintegrin and metalloprotease with thrombospondin motifs protein 1 (ADAMTS1) is a protease commonly up-regulated in metastatic carcinoma. Its overexpression in cancer cells promotes experimental metastasis, but whether ADAMTS1 is essential for metastatic progression is unknown. To address this question, we investigated mammary cancer progression and spontaneous metastasis in the MMTV-PyMT mouse mammary tumor model in Adamts1 knockout mice. Adamts1(-/-)/PyMT mice displayed significantly reduced mammary tumor and lung metastatic tumor burden and increased survival, compared with their wild-type and heterozygous littermates. Histological examination revealed an increased proportion of tumors with ductal carcinoma in situ and a lower proportion of high-grade invasive tumors in Adamts1(-/-)/PyMT mice, compared with Adamts1(+/+)/PyMT mice. Increased apoptosis with unaltered proliferation and vascular density in the Adamts1(-/-)/PyMT tumors suggested that reduced cell survival accounts for the lower tumor burden in ADAMTS1-deficient mice. Furthermore, Adamts1(-/-) tumor stroma had significantly lesser amounts of proteolytically cleaved versican and increased numbers of CD45(+) leukocytes. Characterization of immune cell gene expression indicated that cytotoxic cell activation was increased in Adamts1(-/-) tumors, compared with Adamts1(+/+) tumors. This finding is supported by significantly elevated IL-12(+) cell numbers in Adamts1(-/-) tumors. Thus, in vivo ADAMTS1 may promote mammary tumor growth and progression to metastasis in the PyMT model and is a potential therapeutic target to prevent metastatic breast cancer.
- St. Vincent's Health System United States
- Queensland University of Technology Australia
- Hudson Institute of Medical Research Australia
- Monash University Australia
- Monash Institute of Medical Research Australia
Lung Neoplasms, Knockout, T-Lymphocytes, Apoptosis, Kaplan-Meier Estimate, Inbred C57BL, Mammary tumour growth, Experimental, Mice, breast cancer, Versicans, ADAMTS1 Protein, metastasis, Animals, Neovascularization, Cell Proliferation, Pathologic, Mice, Knockout, Neovascularization, Pathologic, Mammary Neoplasms, Mammary Neoplasms, Experimental, Th1 Cells, Protease Gene, Tumor Burden, Mice, Inbred C57BL, ADAM Proteins, ADAMTS1, Lymphatic Metastasis, Disease Progression, Leukocyte Common Antigens, Female
Lung Neoplasms, Knockout, T-Lymphocytes, Apoptosis, Kaplan-Meier Estimate, Inbred C57BL, Mammary tumour growth, Experimental, Mice, breast cancer, Versicans, ADAMTS1 Protein, metastasis, Animals, Neovascularization, Cell Proliferation, Pathologic, Mice, Knockout, Neovascularization, Pathologic, Mammary Neoplasms, Mammary Neoplasms, Experimental, Th1 Cells, Protease Gene, Tumor Burden, Mice, Inbred C57BL, ADAM Proteins, ADAMTS1, Lymphatic Metastasis, Disease Progression, Leukocyte Common Antigens, Female
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