title: The ADAMTS1 protease gene is required for mammary tumor growth and metastasis.
abstract: 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.
authors: School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors: Carmela
authors: C
authors: Ricciardelli
authors: Kate M
authors: KM
authors: Frewin
authors: Izza de Arao
authors: Ide A
authors: Tan
authors: Elizabeth D
authors: ED
authors: Williams
authors: Kenneth
authors: K
authors: Opeskin
authors: Melanie A
authors: MA
authors: Pritchard
authors: Wendy V
authors: WV
authors: Ingman
authors: Darryl L
authors: DL
authors: Russell
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071097:ADAMTS1 Protein; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D053208:Kaplan-Meier Estimate; D017493:Leukocyte Common Antigens; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D047368:Tumor Burden / Q000235:genetics; D053675:Versicans / Q000378:metabolism
chemical_list: D053675:Versicans; D017493:Leukocyte Common Antigens; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human