Investigating the Role of the Inhibitor of Apoptosis Proteins (IAPs) in Metastasis Formation

Inhibitor of apoptosis proteins (IAPs) constitute a conserved family of molecules, which regulate both apoptosis and receptor signalling. They are often deregulated in cancer cells and represent potential targets for therapy. In my work, I investigated the effect of IAP inhibition <i>in vivo</i> to identify novel down-stream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple negative breast cancer (TNBC) cell line MDA-MB231 were treated with SM83, a Smac mimetic developed in our laboratory that acts as a pan-IAP inhibitor, and tumour nodules were profiled for gene expression. The analysis revealed that the inhibition of IAPs significantly reduces the expression of SNAI2, a zinc finger transcriptional repressor often associated with cancer aggressiveness, resistance to therapy and metastatic potential, especially in breast cancer. By testing several TNBC cell lines, I found that SNAI2 levels is promoted specifically by cellular IAP1 (cIAP1), and not by other IAPs, and that SM83-dependent down-regulation of SNAI2 reduces cancer cell motility. Accordingly, cIAP1 depletion blocks epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway causing the reduction of SNAI2 transcription levels. The inhibition of EGFR signalling stems from the block of receptor signalling and from the down-regulation of its levels, but paradoxically the silencing of cIAP1 promotes EGFR stability rather than its degradation. Nonetheless, EGFR levels decrease upon cIAP1 silencing due to reduced NF-kB-dependent gene expression supporting the notion that cIAP1 controls EGFR in an opposite fashion, promoting its gene expression while causing its degradation. In conclusion, my work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its down-stream mediators. This approach could be particularly effective in tumours characterized by high levels of EGFR and SNAI2, such as TNBCs.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

The Open University

Year dc:date.issued

2018

Author dc:creator

• Majorini, Maria Teresa

Language dc:language

en