ADAMTS18 缺乏与细胞外基质功能障碍相关，增加了 HER2 阳性乳腺肿瘤发生和转移的风险。
ADAMTS18 deficiency associates extracellular matrix dysfunction with a higher risk of HER2-positive mammary tumorigenesis and metastasis.
机构信息
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Science, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, China.
出版信息
Breast Cancer Res. 2024 Jan 29;26(1):19. doi: 10.1186/s13058-024-01771-3.
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/Adamts18) and Adamts18-wildtype (MMTV)-Her2/ErbB2/Neu transgenic mice (i.e., Her2/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/Adamts18 mammary tumor cells are significantly higher than those of primary Her2/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/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.
背景
人表皮生长因子受体 2（HER2）阳性乳腺癌约占所有乳腺癌病例的 20%，与高复发率和预后不良相关。ADAMTS18 被认为是一种重要的功能性肿瘤抑制基因，涉及多种恶性肿瘤，包括乳腺癌。它作为细胞外基质（ECM）调节剂发挥作用。然而，ADAMTS18 是否通过其基本的 ECM 调节功能影响乳腺肿瘤发生和恶性进展尚不清楚。
方法
为了阐明 ADAMTS18 在 HER2 阳性乳腺肿瘤发生和转移中的作用，我们比较了 Adamts18 敲除（MMTV）-Her2/ErbB2/Neu 转基因小鼠（即 Her2/Adamts18）和 Adamts18 野生型（MMTV）-Her2/ErbB2/Neu 转基因小鼠（即 Her2/Adamts18）之间乳腺肿瘤和转移的发生率。通过病理学、细胞培养、Western blot 和免疫组化研究了 ADAMTS18 调节 HER2 阳性肿瘤发生和转移的潜在机制。
结果
ADAMTS18 mRNA 主要在乳腺导管的肌上皮细胞中表达。ADAMTS18 缺陷导致乳腺肿瘤和转移的发生率以及小鼠乳腺增生显著增加，在 30 个月的观察中观察到。体外 Her2/Adamts18 原发性乳腺肿瘤细胞的增殖、迁移和侵袭能力明显高于 Her2/Adamts18 原发性乳腺肿瘤细胞。在 30 个月时，Her2/Adamts18 小鼠乳腺中层粘连蛋白（LNα5）、纤维连接蛋白（FN）和 I 型胶原（ColI）的表达水平显著增加，整合素介导的 PI3K/AKT、ERK 和 JNK 信号通路的活性增强。
结论
ADAMTS18 缺陷导致乳腺 ECM 成分（如 LNα5、FN、ColI）的改变，与 HER2 阳性乳腺肿瘤发生和转移的风险增加相关。
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