XIAP is the most potent caspase inhibitor of all of the IAPs, and blocks both the intrinsic and extrinsic apoptosis pathways by binding to caspases 3, 7 and 9. Currently there are surpris ingly few studies on XIAP in breast cancer, and these few have focused on a limited number of cell lines, to our knowledge, (-)-Nutlin-3 only one other study has examined its in vivo expression in comparison with normal breast, where XIAP positivity corre lated with tumour grade. As with previous studies in the breast cancer cell lines and in the National Cancer Institute panel of tumour cell lines, we found that XIAP expression was variable. This variability possibly reflects the mul tiple mechanisms by which XIAP can be regulated, all of which or some of which may be altered in cancer.

Despite this varia bility in the cell line panel, XIAP was more markedly upregu lated in a subset of Inhibitors,Modulators,Libraries the breast tumour samples compared with normal tissue. In the case of cIAP1, there was a marked upregulation in the cancer cell lines compared with MCF10a cells. No such upregulation was seen, however, in the tumour panel. The present study is the first that has examined Inhibitors,Modulators,Libraries cIAP1 protein in breast tumour biopsies and compared its expression between normal breast epithelia and breast cancer samples Inhibitors,Modulators,Libraries or cell lines. Interestingly, we found that cIAP2 was lower in the can cer cell lines versus normal cell lines and in the tumour tissue versus normal tissue samples. Future studies involving greater patient num bers with matched cancer and normal tissue samples are required to confirm the variation in cIAP1 and the possible downregulation of cIAP2 in invasive carcinomas.

Overall, these data demonstrate Inhibitors,Modulators,Libraries that multiple IAPs are expressed in breast cancer and therefore are potentially responsible for apoptotic resistance. IAPs, in particular XIAP and cIAPs, are therefore potential targets for lowering the apoptotic threshold of breast cancers, making them more sen sitive to therapeutic drugs. We confirmed this hypothesis by examining TRAIL induced apoptosis in the presence or absence of an XIAP siRNA or a Smac mimetic. Importantly, this had a major effect in one cell line the MDAMB468 cells. The Smac mimetic has also been shown to substantially increase TRAIL induced apoptosis in the MDAMB231 cell line. Interestingly both the MDAMB468 and MDAMB231 cells are triple negative cell lines.

In BT474 cells and BT20 cells, which did not appear to have elevated levels of XIAP, inhibition Inhibitors,Modulators,Libraries of XIAP also increased TRAIL induced apoptosis, suggesting that XIAP does not need to be overexpressed for the Smac mimetic to be of use. Of potential clinical impor tance, neither TRAIL nor the Smac mimetic had any effect in the MCF10a cell line. Inhibitors of apoptosis and ErbB antagonists Only a few studies have looked at combining XIAP inhibitors with targeted therapies to growth factor Calcitriol chemical structure receptors.