Abstract P3-15-04: Signalling pathways targeted by the YangZheng Xiaoji extract and the therapeutic implications in human breast cancer

Background. Yangzheng Xiaoji is a formulation of Chinese medicine and has been used in the treatment of solid cancer as an adjuvant to chemotherapy by reducing the side effects to the patient. There has been evidence to show that the medicine has a direct biological role in cancer cells. In the present study, we sought to investigate the potential effects of the medicine on breast cancer cells and in particular aimed to identify the key targets and molecular pathways contributing to the anti-cancer effect of the medicine. Methods. Human breast cancer cell lines (BT549, BT20, MDA MB-231, MCF-7 and ZR 75-1) with varying invasiveness and receptor status were used. The soluble extract of Yangzheng Xiaoji , namely DME25 was used in the study. The effects of DME25 on the growth, toxicity and cellular migration were assessed. Signalling kinase changes were screened using kinase antibody array based array technologies. Kinases were also validated using phosphorylation based protein blotting. Results. Of the five breast cancer cell lines tested, Yangzheng Xiaoji extract DME25 showed little cytotoxicity over a broad range of concentrations. However, DME25 were able to markedly reduce the migration of the panel of breast cancer tested, without being toxic. Triple negative cells responded in a similar fashion with other cells. It was also noted that the adhesion of these cells were also inhibited by DME25. Using a protein kinase array, it was shown that a number of kinase complexes were inhibited by the medicine, notable ones including EGFR family kinases (reduced by 35%), Janus protein kinases (JAK) (by 57%), and Ras-related C3 botulinum toxin substrate (Rac1 or CDC42 GTPase) (by 49%) and Ribosomal protein S6 kinases (RSKs) (by 52%). Given the clinical significance of RSKs in human breast cancer, we further evaluated the role of RSK and RSK inhibitors in DME mediated cell functions and have demonstrated that both in triple negative breast cancer cells and receptor positive breast cancer cell lines, DME25 was able to synergistically enhance the effect of RSK2 inhibitor, SL1010-1, on the both the cellular migration and cell growth. Conclusion. Yangzheng Xiaoji has a broad and direct effect on the migration of breast cancer, an effect unrelated to hormone receptor status and independent of cytotoxicity. The medicine appears to target kinase pathway, particularly for the RSK kinases, suggesting an important clinical implication in the treatment of breast cancer. Citation Format: Jiang WG, Ye L, Owen S, Ruge F, Martin TA, Sanders AJ, Gao G, Wei C, Wu Y, Davies E. Signalling pathways targeted by the YangZheng Xiaoji extract and the therapeutic implications in human breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-15-04.