We evaluated the levels and possible associations of seven parameters including the status of the TOP1 gene (i.e. amplification), TOP1 protein expression level, TOP1 activity and CPT susceptibility, activity of the tyrosyl-DNA phosphodiesterase 1 (TDP1), the cellular CPT response and the cellular growth rate across a representative panel of BC cell lines, which exemplifies three major BC subtypes: Luminal, HER2 and TNBC.
Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC).
To reveal the functions of human Top1, we have generated stable Top1 small interfering RNA (siRNA) cell lines from colon and breast carcinomas (HCT116-siTop1 and MCF-7-siTop1, respectively).
The breast cancer cell line ZR-75-1, the most sensitive to CPT, was completely defective in CPT-induced TOP1 down-regulation, whereas the breast cancer cell line BT474, the least sensitive to CPT, exhibited effective CPT-induced TOP1 down-regulation.
Recently, natural product DNA topoisomerase I inhibitors 10-hydroxycamptothecin (HCPT) and camptothecin (CPT) have been shown to have therapeutic effects in both in vitro and in vivo models of human breast cancer.