背景:人类表皮生长因子受体2(HER2)阳性乳腺癌约占所有乳腺癌病例的20%,并且与高复发率和不良预后相关。ADAMTS18被认为是参与多种恶性肿瘤的重要功能抑癌基因,包括乳腺癌.其作为细胞外基质(ECM)调节剂起作用。然而,目前尚不清楚ADAMTS18是否通过其必要的ECM调节功能影响乳腺肿瘤发生和恶性进展.
方法:为了阐明ADAMTS18在HER2阳性乳腺肿瘤发生和体内转移中的作用,我们比较了Adamts18基因敲除(MMTV)-Her2/ErbB2/Neu转基因小鼠之间的乳腺肿瘤发生率和转移(即,Her2t/w/Adamts18-/-)和Adamts18-野生型(MMTV)-Her2/ErbB2/Neu转基因小鼠(即,Her2t/w/Adamts18+/+)。通过病理学研究了ADAMTS18调节HER2阳性肿瘤发生和转移的潜在机制,细胞培养,蛋白质印迹和免疫化学。
结果:Adamts18mRNA主要在乳腺导管的肌上皮细胞中表达。ADAMTS18缺乏导致乳腺肿瘤和转移的发生率显着增加,以及小鼠的乳腺增生,超过30个月的观察。扩散,原代Her2t/w/Adamts18-/-乳腺肿瘤细胞的迁移和侵袭能力明显高于原代Her2t/w/Adamts18+/+乳腺肿瘤细胞。在30个月大的时候,层粘连蛋白(LNα5)的表达水平,Her2t/w/Adamts18-/-小鼠乳腺内纤连蛋白(FN)和Ⅰ型胶原(ColI)显著增高,和整合素介导的PI3K/AKT的活性,ERK和JNK信号通路增强。
结论:ADAMTS18缺乏导致乳腺ECM成分的改变(例如,LNα5,FN,ColI),这与HER2阳性乳腺肿瘤发生和转移的高风险相关。
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.
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., Her2t/w/Adamts18-/-) and Adamts18-wildtype (MMTV)-Her2/ErbB2/Neu+ transgenic mice (i.e., Her2t/w/Adamts18+/+). The underlying mechanisms by which ADAMTS18 regulates HER2-positive tumorigenesis and metastasis were investigated by pathology, cell culture, Western blot and immunochemistry.
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 Her2t/w/Adamts18-/- mammary tumor cells are significantly higher than those of primary Her2t/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 Her2t/w/Adamts18-/- mice are significantly increased, and the activities of integrin-mediated PI3K/AKT, ERK and JNK signaling pathways are enhanced.
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.