Department of Pathology and Pathophysiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
Department of Oncology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China.
Cancer Med. 2019 Apr;8(4):1679-1693. doi: 10.1002/cam4.2019. Epub 2019 Feb 25.
Breast cancer is one of the most common malignant tumors among women worldwide. About 70-75% of primary breast cancers belong to estrogen receptor (ER)-positive breast cancer. In the development of ER-positive breast cancer, abnormal activation of the ERα pathway plays an important role and is also a key point leading to the failure of clinical endocrine therapy. In this study, we found that the small molecule peptide chlorotoxin (CTX) can significantly inhibit the proliferation, migration and invasion of breast cancer cells. In in vitro study, CTX inhibits the expression of ERα in breast cancer cells. Further studies showed that CTX can directly bind to ERα and change the protein secondary structure of its LBD domain, thereby inhibiting the ERα signaling pathway. In addition, we also found that vasodilator stimulated phosphoprotein (VASP) is a target gene of ERα signaling pathway, and CTX can inhibit breast cancer cell proliferation, migration, and invasion through ERα/VASP signaling pathway. In in vivo study, CTX significantly inhibits growth of ER overexpressing breast tumor and, more importantly, based on the mechanism of CTX interacting with ERα, we found that CTX can target ER overexpressing breast tumors in vivo. Our study reveals a new mechanism of CTX anti-ER-positive breast cancer, which also provides an important reference for the study of CTX anti-ER-related tumors.
乳腺癌是全世界女性最常见的恶性肿瘤之一。约 70-75%的原发性乳腺癌属于雌激素受体（ER）阳性乳腺癌。在 ER 阳性乳腺癌的发展过程中，ERα 通路的异常激活发挥着重要作用，也是导致临床内分泌治疗失败的关键点。在本研究中，我们发现小分子肽氯毒素（CTX）可显著抑制乳腺癌细胞的增殖、迁移和侵袭。在体外研究中，CTX 抑制乳腺癌细胞中 ERα 的表达。进一步的研究表明，CTX 可以直接与 ERα 结合并改变其 LBD 结构域的蛋白质二级结构，从而抑制 ERα 信号通路。此外，我们还发现血管扩张刺激磷蛋白（VASP）是 ERα 信号通路的靶基因，CTX 通过 ERα/VASP 信号通路抑制乳腺癌细胞的增殖、迁移和侵袭。在体内研究中，CTX 显著抑制 ER 过表达乳腺癌肿瘤的生长，更重要的是，基于 CTX 与 ERα 相互作用的机制，我们发现 CTX 可以在体内靶向 ER 过表达的乳腺癌肿瘤。我们的研究揭示了 CTX 抗 ER 阳性乳腺癌的新机制，也为 CTX 抗 ER 相关肿瘤的研究提供了重要参考。
