Abstract P3-06-10: The impact of the Chinese medicine ShenLingLan on triple negative breast cancer, the metabolic and signalling pathways and clinical implications

Abstract

Abstract Background. Triple negative breast cancer (TNBC) is a challenging both in the choice of therapies and clinical outcomes. In the present study, we investigated the potential prospect of a Chinese medicine formation, ShenLingLan, shown to have benefit to patients with cancer and able to influence the biological behaviour of cancer cells, on breast cancer cells in particular the differential response from TNBC and non-TNBC cells and, on the discovery that TNBC cells were particularly sensitive to the medicine, we went on to determine the signalling and mechanism of action. Methods. A panel of three TNBC (MDA MB-231, BT20 and BT549) and a panel of three non-TNBC (MCF-7, ZR 75-1 and T47D) cells were used. A soluble extract from ShenLingLan, designated as SLDM, was utilised during this study. The proliferation, cellular migration and adhesiveness were tested using conventional and biophysical methods. Signalling profiling was conducted using a protein kinase array platform (Kinexustm). Metabolic profiling was conducted using the Seahorse platform. Expression of insulin receptor (IR) and insulin-like growth factor receptor (IGFR) gene transcripts (quantitative transcript analysis) and proteins (IHC) were conducted using a fresh breast cancer cohort and tissue array, respectively. Results. SLDM had little effects on the growth of breast cancer cells. However, it had profound inhibitory effects on the migration of both TNBC and non-TNBC cells in a concentration dependent manner. Interestingly, TNBC cells were 5-20 times more sensitive than the non-TNBC cells in their migration and cell adhesion responses to SLDM. The protein array platform further revealed that, of the wide range of protein kinases, IR and IGRR1 were the most affected in that SLDM resulted in 25-50% reduction in the phosphorylation of IR and IR substrate in TNBC cells. SLDM also caused a contrasting response in IGFR1 phosphorylation in TNBC and non-TNBC cells. Metabolically, TNBC and non-TNBC cells responded to SLDM in very different fashions. For example, in TNBC cells SLDM resulted in a significant decrease in glycolytic activities, in particular that driven by insulin (30.2±12.2 pmol/min in control, 47.7±10 pmol/min with insulin and 35.4±4.2 pmol/min with insulin/SLDM, p=0.01). There is evidence that the mitochondria oxygen consumption (OCR) was also affected by SLDM in TNBC cells (p=0.01). These changes induced by SLDM were in clear contrast to non-TNBC cells which did not respond with significant reduction. Both TNBC and non-TNBC breast cancer tissues have higher IR staining than normal mammary tissues (p<0.001). TNBC tumours also demonstrated significantly more positive IR staining than the non-TNBC tumours (p=0.04). Conclusion. ShenLingLan has a profound inhibitory effect on the migration and cell-matrix adhesion of TNBC cells, with marked effect on the metabolics of these cells. This effect connects with reduction of the IR and IGFR activation, mainly through the reduction in glycolysis. Together with the clinical implication of IR and IGFR in breast cancer, ShenLingLan has an important role in the treatment of breast cancer with an emphasis in TNBCs. Citation Format: Jiang WG, Owen S, Ruge F, Gao Y, Wang H, Wei C, Wu Y, Davies E. The impact of the Chinese medicine ShenLingLan on triple negative breast cancer, the metabolic and signalling pathways and clinical implications [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 P3-06-10.