Inhibitor of apoptosis proteins in breast cancer

Background and methods

Resistance to apoptosis is a hallmark of cancer. Decreased sensitivity to apoptosis leads to an elevated therapeutic threshold for classical interventions such as chemotherapy or radiotherapy. The Inhibitor of Apoptosis Proteins (IAPs) are a family of proteins that prevent caspases from inducing apoptosis. Targeting IAPs therefore represents a potential avenue for reducing the threshold to apoptosis and improving therapeutic effectiveness. There are eight human IAP family members, including XIAP, Survivin, cIAP1, cIAP2, Livin, NAIP and Apollon. Although some studies have indicated altered levels of Survivin and XIAP in several tumour models, no study to date has examined the role of all members of the IAP family in cancer progression. We aim (i) to investigate the expression of the whole family of IAPs across a wide range breast cancer cell lines and tumour samples at both the RNA and protein level, and (ii) to determine whether targeting IAPs alters susceptibility to apoptosis.

Results

Preliminary results confirm that the levels of Survivin and XIAP vary across a breast cancer cell line panel. Expression of the other IAP family members is currently being determined.

IAP expression will be correlated to the ER, PR, p53, Erb2, and EGFR status of the cell lines and tumours, to determine whether there is a relationship between IAP expression and prognostic indicators. Overexpression and siRNA-induced knockdown approaches will be used to investigate whether altering the expression of IAPs identified in our original screen affects the apoptotic threshold in response to various chemotherapeutic agents. This will be examined using both 2D and 3D cell culture systems.