Chlorotoxin targets ERα/VASP signaling pathway to combat breast cancer

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 ER alpha 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 ER alpha in breast cancer cells. Further studies showed that CTX can directly bind to ER alpha and change the protein secondary structure of its LBD domain, thereby inhibiting the ER alpha signaling pathway. In addition, we also found that vasodilator stimulated phosphoprotein (VASP) is a target gene of ER alpha signaling pathway, and CTX can inhibit breast cancer cell proliferation, migration, and invasion through ER alpha/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 ER alpha, 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.