Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan.
Division of Family Medicine, Physical Examination Center, China Medical University Hsinchu Hospital, Hsinchu, Taiwan.
Environ Toxicol. 2024 Jun;39(6):3389-3399. doi: 10.1002/tox.24202. Epub 2024 Mar 6.
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.
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，赋予肿瘤更具侵袭性的表型，并与预后不良相关。接受 HER2 酪氨酸激酶抑制剂（HER2 TKIs）治疗的转移性乳腺癌患者，如拉帕替尼，在一年内会产生获得性耐药，这对这种疾病的治疗构成了重大挑战。在这里，我们探讨了一种具有抗癌特性的中草药——艾草，在减轻乳腺癌中 HER2 TKI 耐药性方面的潜力。癌症基因组图谱（TCGA）的分析显示，乳腺癌患者中跨膜丝氨酸蛋白酶 2（TMPRSS2）的表达减少，TMPRSS2 是膜蛋白水解酶的一个亚家族，与不良预后相关。有趣的是，拉帕替尼应答患者表现出更高的 TMPRSS2 表达。我们的研究揭示了艾草中的化合物，如橙皮苷和伞形酮，可以抑制拉帕替尼耐药的 HER2 阳性乳腺癌细胞的生长。从机制上讲，它们通过增强 TMPRSS2 活性来抑制 HER2 激酶的激活。我们的研究结果表明 TMPRSS2 是拉帕替尼敏感性的关键决定因素，而艾草作为一种通过激活 HER2 阳性乳腺癌中的 TMPRSS2 来克服拉帕替尼的潜在药物出现。这项研究不仅揭示了艾草诱导的 HER2 阳性乳腺癌细胞死亡的分子机制，也为开发新型抑制剂以增强治疗效果奠定了基础。
