The ADAMTS1 protease gene is required for mammary tumor growth and metastasis

Ricciardelli, Carmela, Frewin, Kate M., Tan, Izza de Arao, Williams, Elizabeth D., Opeskin, Kenneth, Pritchard, Melanie A., Ingman, Wendy V., & Russell, Darryl L. (2011) The ADAMTS1 protease gene is required for mammary tumor growth and metastasis. The American Journal of Pathology, 179(6), pp. 3075-3085.

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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.

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ID Code: 77755
Item Type: Journal Article
Refereed: Yes
Keywords: ADAMTS1, Protease Gene, Mammary tumour growth, breast cancer, metastasis
DOI: 10.1016/j.ajpath.2011.08.021
ISSN: 0002-9440
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Genetics (111203)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2011 American Society for Investigative Pathology
Deposited On: 16 Oct 2014 05:07
Last Modified: 12 Feb 2015 00:28

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