ADAMTS18 deficiency associates extracellular matrix dysfunction with a higher risk of HER2-positive mammary tumorigenesis and metastasis

Background: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for about 20% of all breast cancer cases and is correlated with a high relapse rate and poor prognosis. ADAMTS18 is proposed as an important functional tumor suppressor gene involved in multiple malignancies, including breast cancer. It functions as an extracellular matrix (ECM) modifier. However, it remains unclear whether ADAMTS18 affects mammary tumorigenesis and malignant progression through its essential ECM regulatory function. Methods: To elucidate the role of ADAMTS18 in HER2-positive mammary tumorigenesis and metastasis in vivo, we compared the incidence of mammary tumor and metastasis between Adamts18-knockout (MMTV)-Her2/ErbB2/Neu⁺ transgenic mice (i.e., Her2^t/w/Adamts18^−/−) and Adamts18-wildtype (MMTV)-Her2/ErbB2/Neu⁺ transgenic mice (i.e., Her2^t/w/Adamts18^+/+). The underlying mechanisms by which ADAMTS18 regulates HER2-positive tumorigenesis and metastasis were investigated by pathology, cell culture, Western blot and immunochemistry. Results: Adamts18 mRNA is mainly expressed in myoepithelial cells of the mammary duct. ADAMTS18 deficiency leads to a significantly increased incidence of mammary tumors and metastasis, as well as mammary hyperplasia in mice, over 30 months of observation. The proliferation, migration and invasion capacities of primary Her2^t/w/Adamts18^−/− mammary tumor cells are significantly higher than those of primary Her2^t/w/Adamts18^+/+ mammary tumor cells in vitro. At 30 months of age, the expression levels of laminin (LNα5), fibronectin (FN) and type I collagen (ColI) in the mammary glands of Her2^t/w/Adamts18^−/− mice are significantly increased, and the activities of integrin-mediated PI3K/AKT, ERK and JNK signaling pathways are enhanced. Conclusions: ADAMTS18 deficiency leads to alterations in mammary ECM components (e.g., LNα5, FN, ColI), which are associated with a higher risk of HER2-positive mammary tumorigenesis and metastasis.