Crosstalk and modulation of signaling between somatostatin and growth factor receptors in human breast cancer cell lines

The molecular mechanisms of breast cancer are poorly understood, which present serious therapeutic problems and complicates drug design. Cell surface receptors belonging to G-protein-coupled receptor (GPCR) and receptor tyrosine kinase (RTK) families are potential drug targets relevant to pathological conditions, and have attracted great interest from pharmaceutical industry. Recent studies have suggested that somatostatin (SST) receptors (SSTR1-5) belonging to GPCR family may interact with human epidermal growth factor (EGF) receptors (ErbB 1-4) from RTK family in pathophysiological conditions, exerting antiproliferative effects that may be useful in the treatment of breast cancers. An understanding of molecular mechanisms responsible for these effects reveal new approaches to the design of efficient breast cancer therapies that would significantly improve the lives of patients. The work presented in this thesis was conducted to investigate crosstalk between SSTR and ErbB proteins in BT-474 and SK-BR-3 breast cancer cell lines upon SST and/or EGF treatment, to clarify the underlying molecular mechanisms, and to explore their implications for cancer therapy. Several pairs of SSTR and ErbB proteins exhibited strong membrane coexpression and crosstalk in the presence of the tested ligands, including SSTR2/ErbB1, SSTR3/ErbB2, and SSTR5/ErbB3 in BT-474 cells, and SSTR5/ErbB1 in SK-BR-3 cells. New crosstalk processes between SSTR and ErbB subtypes were observed in both cell lines. In BT-474 cells, there were substantial reductions in the membrane expression of ErbB1 (degradation and termination of signaling) and ErbB2, as well as moderately reduced expression of ErbB3 and greatly enhanced activation of SSTR1 and SSTR4. Similarly, SK-BR-3 cells exhibited strong reductions in the expression of ErbB1 (degradation), ErbB3, and ErbB2 expression (partial degradation), while enhanced activation of SSTR1 and SSTR2 expression at the cell surface. The activated SSTRs were shown to antagonize ErbB-mediated MAPK signaling and tumor-promoting signaling pathways, resulting in pronounced antiproliferative effects. In BT-474 cells, they inhibited ERK1/2, p38 and PI3K, and enhanced PTEN pathways, while in SK-BR-3 cells they promoted ERK1/2 and p38, inhibited PI3K and maintained PTEN pathways. These results show that the activated SSTRs exert antiproliferative effects in breast cancer cells via mechanisms that resemble those determined for drugs modulating cancer-related signaling pathways.Pharmaceutical Sciences, Faculty ofGraduat