Abstract：
Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes.
摘要：
乳腺癌是全球女性中主要的恶性肿瘤和癌症相关死亡的主要原因。大约25%的乳腺癌表现出HER2过表达，赋予更具侵袭性的肿瘤表型，并与不良预后相关。接受HER2酪氨酸激酶抑制剂（HER2TKIs）治疗的转移性乳腺癌患者，比如拉帕替尼，在一年内产生获得性抗性，在管理这种疾病方面构成了严峻的挑战。这里,我们探索艾蒿的潜力，一种以抗癌特性闻名的中草药，减轻乳腺癌HER2TKI耐药。癌症基因组图谱（TCGA）的分析显示，跨膜丝氨酸蛋白酶2（TMPRSS2）的表达减少，膜蛋白水解酶的一个亚家族，在乳腺癌患者中，与不利结果相关。有趣的是，拉帕替尼反应性患者表现出更高的TMPRSS2表达。我们的研究揭示了来自Artemisiaargyi的化合物，安的酚,伞形酮可以抑制拉帕替尼耐药HER2阳性乳腺癌细胞的生长。机械上,他们通过增强TMPRSS2活性抑制HER2激酶激活。我们的研究结果提出TMPRSS2是拉帕替尼敏感性的关键决定因素，在HER2阳性乳腺癌中,艾蒿通过激活TMPRSS2作为一种潜在的药物来克服拉帕替尼。这项研究不仅揭示了艾蒿诱导的HER2阳性乳腺癌细胞中驱动细胞死亡的分子机制，而且为开发新型抑制剂以增强治疗效果奠定了基础。
