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

IF 7.4 1区 医学 Q1 Medicine
Jiahui Nie, Suying Dang, Rui Zhu, Tiantian Lu, Wei Zhang
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引用次数: 0

Abstract

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., 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.

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 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.

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.

ADAMTS18 缺乏会导致细胞外基质功能障碍,从而增加 HER2 阳性乳腺肿瘤发生和转移的风险。
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%,且复发率高、预后差。ADAMTS18 被认为是一种重要的功能性肿瘤抑制基因,与包括乳腺癌在内的多种恶性肿瘤有关。它的功能是细胞外基质(ECM)修饰剂。然而,ADAMTS18是否通过其重要的ECM调控功能影响乳腺肿瘤的发生和恶性进展仍不清楚:为了阐明 ADAMTS18 在体内 HER2 阳性乳腺肿瘤发生和转移中的作用,我们比较了 Adamts18 基因敲除(MMTV)-Her2/ErbB2/Neu+ 转基因小鼠(即、Her2t/w/Adamts18-/-)和 Adamts18 野生型(MMTV)-Her2/ErbB2/Neu+ 转基因小鼠(即 Her2t/w/Adamts18+/+)之间的乳腺癌和转移。研究人员通过病理学、细胞培养、Western印迹和免疫化学等方法探讨了ADAMTS18调控HER2阳性肿瘤发生和转移的内在机制:结果:Adamts18 mRNA主要表达于乳腺导管的肌上皮细胞。在 30 个月的观察中,ADAMTS18 缺乏会导致小鼠乳腺肿瘤和转移以及乳腺增生的发生率显著增加。原代Her2t/w/Adamts18-/-乳腺肿瘤细胞在体外的增殖、迁移和侵袭能力明显高于原代Her2t/w/Adamts18+/+乳腺肿瘤细胞。30月龄时,Her2t/w/Adamts18-/-小鼠乳腺中层粘蛋白(LNα5)、纤连蛋白(FN)和I型胶原(ColI)的表达水平明显升高,整合素介导的PI3K/AKT、ERK和JNK信号通路的活性增强:结论:ADAMTS18 缺乏会导致乳腺 ECM 成分(如 LNα5、FN、ColI)的改变,这与 HER2 阳性乳腺肿瘤发生和转移的高风险有关。
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来源期刊
CiteScore
12.00
自引率
0.00%
发文量
76
审稿时长
12 weeks
期刊介绍: Breast Cancer Research, an international, peer-reviewed online journal, publishes original research, reviews, editorials, and reports. It features open-access research articles of exceptional interest across all areas of biology and medicine relevant to breast cancer. This includes normal mammary gland biology, with a special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal covers preclinical, translational, and clinical studies with a biological basis, including Phase I and Phase II trials.
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