| Summary: | Epidermal growth factor receptor (ErbB1) and somatostatin receptors (SSTRs) exert opposing effects on tumor promoting signaling pathways. Whether SSTRs functionally interact with ErbB1 and modulate tumor-promoting signaling is currently unknown. For this reason, the specific emphasis of this thesis is to examine the role of SSTRs in ErbB1 mediated signaling in breast cancer cells and human embryonic kidney (HEK) 293 cells. First, I determined the mRNA and protein expression of SSTR1, SSTR5 and ErbB1 in human breast cancer cell lines namely MCF-7 and MDA-MB231. I next demonstrated that SSTR1 or 5 exist as pre-formed heterodimers with ErbB1, which dissociated in an agonist dependent manner. Somatostatin (SST) modulated epidermal growth factor (EGF) mediated MAPK in a time and agonist dependent manner. Furthermore, SST and/or EGF treatment altered the expression of key adapter proteins including Grb2, SOS, Shc, SH-PTP1 and SH-PTP2, which are known to play a role in MAPK activation. Since breast cancer cells endogenously express SSTR and ErbB subtypes, this study was further extended in HEK-293 to gain insight into the effect of individual SSTR on ErbB1 activated signaling. We demonstrated that HEK-293 cells transfected with SSTR1, SSTR5 or SSTR1/5 negatively regulate EGF mediated effects attributed to the inhibition of ErbB1 phosphorylation, MAPKs and PI3K/AKT pathways. Moreover, SST effects were significantly enhanced in cells when ErbB1 was knocked down using small interference ribonucleic acid (siRNA) or treated with selective ErbB1 antagonist (AG1478). The presence of SSTRs, in addition to modulating signaling pathways, led to the dissociation of constitutive and EGF induced heteromeric complex of ErbB1/ErbB2. Most significantly, cells co-transfected with SSTR1/5 display pronounced effects of SST on the signaling and dissociation of the ErbB1/ErbB2 heteromeric complex than cells expressing either SSTR1 or 5 alone.
The findings of this study discovered a new mechanism and potential role of SSTRs in attenuation of ErbB1 mediated signaling pathways via dissociation of ErbB1/ErbB2 heteromeric complex. In conclusion, the results presented in this thesis suggest that formulating novel drugs that activate SSTRs along with inhibition of ErbB1 might likely serve as an important therapeutic approach in the treatment of ErbBs positive tumors.
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