Immunohistochemical detection of antiapoptotic protein X-linked inhibitor of apoptosis in mammary carcinoma

Jaffer, Shabnam; Orta, Lurmag; Sunkara, Srinivas; Sabo, Edmond; Burstein, David

doi:10.1016/j.humpath.2006.11.016

Cited by 38 publications

(34 citation statements)

References 27 publications

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“…Perhaps the changes result from the different cellular locations of survivin [32]. Data concerning XIAP indicates that XIAP expression increases with grade of ductal invasive breast carcinoma, as well as ductal breast carcinoma in situ [34] with no relationship to hormonal receptor status. The ambiguity of the role of XIAP protein in breast cancer behavior should be clarified in a larger survey.…”

Section: Discussionmentioning

confidence: 99%

Expression of IAP family proteins and its clinical importance in breast cancer patients

Pluta¹,

Jeziorski²,

Cebula-Obrzut³

et al. 2015

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Inhibitor of apoptosis (IAP) family proteins is involved in mechanisms of resistance to apoptosis in various cancer cells. The aim of this study was to assess the expression of selected IAP proteins such as XIAP, cIAP-1, cIAP-2 and survivin in breast cancer patients and evaluates their relationship with the prognostic and predictive factors and their impact to overall survival (OS) and progression free survival (PFS). The study was conducted with the use of tissue samples prospectively collected from 92 previously untreated female breast cancer patients. The control encompassed 10 fibroadenoma patients. The expression of XIAP, cIAP-1, cIAP-2 and survivin was assessed using flow multicolor cytometry. XIAP expression was present in 99 % of the breast cancer patients (91/92) with the median expression 13.65% (range 1-66.8%). Expression of XIAP in breast cancer was significantly higher compared to the control group (p=0.006). Median expression of cIAP-1, cIAP-2 and survivin in the study group was 25.95% (range 0.8-83.7%), 16.7% (range 1-53.2%) and 4.6% (range 0-43%) respectively. In the rank Spearman test, strong correlations (p<0.001) were seen among the expressions of XIAP, cIAP-2 and survivin, in all combination. Additionally, week correlation between XIAP and cIAP-1 was observed (p=0.02). The median expression of XIAP and survivin was significantly higher in more advanced tumors (stages pT2/pT3 vs. pT1). The median PFS and OS in breast cancer group were 46.15 and 47.1 months respectively. No significant correlations were observed among expressions of IAP family proteins and survival. However, low expression of XIAP in breast cancer showed trend to longer PFS (p=0.08). XIAP, cIAP-1 cIAP-2 and survivin participate in antiapoptotic mechanisms in breast cancer and XIAP and survivin seem to have the most significant prognostic importance. Further studies are needed to establish more complete prognostic and predictive values of IAP family proteins in breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Expression of IAP family proteins and its clinical importance in breast cancer patients

Pluta¹,

Jeziorski²,

Cebula-Obrzut³

et al. 2015

neo

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“…While XIAP is not considered to be a classical oncogene, it has been detected at elevated levels in tumors resistant to chemotherapy and is associated with poor outcome in several cancers [15][16][17][18]. Two broad approaches have been taken to develop clinical inhibitors of XIAP, including antisense …”

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confidence: 99%

Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism

Allensworth

Sauer

Lyerly

et al. 2012

Breast Cancer Res Treat

101

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Abstract:X-linked Inhibitor of Apoptosis Protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAILsensitive SUM149 (triple negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149-and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (Kd >1 µM), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. The above manuscript was initially submitted to Breast Cancer Research and Treatment and the authors received the reviews along with the decision of 'could be accepted for publication should you be prepared to incorporate major revisions'.We thank the reviewer for his recommendations that were indeed helpful in revising this manuscript. We have included a detailed author response and revision status of each of the reviewer's comments.In response to the reviewer's concerns, we have undertaken the following experiments: 1.Measurement of clonogenic growth potential as a means of assessing viability effects of the Smac mimetic treatments 2.Annexin-V/7-AAD flow cytometric staining of cells treated with the Smac mimetics as a direct means of evaluating apoptosis 3.An in-depth time course analysis of NF-kB activation in SUM190 cells following treatment with the Smac mimetic 4.Assessment of anchorage independent growth potential as a preliminary predictor of in vivo activity of the Smac mimeticWe sincerely hope that all the reviewers' concerns have been adequately addressed and the manuscript is acceptable for publication in the present revised form.Disclosure Statement: The authors are aware of and agree to the content of the paper and ...

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“…Elevated expression of XIAP has been demonstrated in cancers of various origins. [10][11][12][13][14][15][16] Not only is XIAP overexpressed in cancer, increased XIAP expression has been shown to contribute to apoptosis resistance and conversely, XIAP antagonism sensitizes cancer cells to multiple types of apoptotic stimuli in vitro and in vivo. 13,[17][18][19][20][21][22][23][24][25]28,[32][33][34][35][36][37] These apoptotic stimuli have included various chemotherapeutic agents, ionizing radiation, tumor necrosis factor-related apoptosis-inducing ligand, anoikis induction and immune clearance by cytotoxic lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] XIAP overexpression has been reported in a variety of human cancers. [10][11][12][13][14][15][16] Increased XIAP levels have been linked to escaping anoikis and apoptosis induced by radiation, chemotherapy and death receptor ligands. 13,[17][18][19][20][21][22] Furthermore, antagonism of XIAP has been reported to have antitumor activity in a number of models, including prostate cancer.…”

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confidence: 99%

X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model

et al. 2008

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Deregulation of apoptotic pathways plays a central role in cancer pathogenesis. X-linked inhibitor of apoptosis protein (XIAP), is an antiapoptotic molecule, whose elevated expression has been observed in tumor specimens from patients with prostate carcinoma. Studies in human cancer cell culture models and xenograft tumor models have demonstrated that loss of XIAP sensitizes cancer cells to apoptotic stimuli and abrogates tumor growth. In view of these findings, XIAP represents an attractive antiapoptotic therapeutic target for prostate cancer. To examine the role of XIAP in an immunocompetent mouse cancer model, we have generated transgenic adenocarcinoma of the mouse prostate (TRAMP) mice that lack XIAP. We did not observe a protective effect of Xiap deficiency in TRAMP mice as measured by tumor onset and overall survival. In fact, there was an unexpected trend toward more aggressive disease in the Xiap-deficient mice. These findings suggest that alternative mechanisms of apoptosis resistance are playing a significant oncogenic role in the setting of Xiap deficiency. Our study has implications for XIAP-targeting therapies currently in development. Greater understanding of these mechanisms will aid in combating resistance to XIAP-targeting treatment, in addition to optimizing selection of patients who are most likely to respond to such treatment. Cell Death and Differentiation (2008) Apoptosis is a process of cell death that is tightly regulated by a cadre of both pro-and antiapoptotic proteins. In contrast to healthy cells, a hallmark of cancerous cells is the acquired capacity to evade this process of programmed cell death. 1,2 The acquisition of genetic lesions leading to oncogene activation normally triggers a program of apoptosis or senescence. Additionally, the tumor microenvironment often exposes malignant cells to apoptotic stimuli, such as hypoxia or activation of death receptors. Thus, suppression of the pathway leading to cell death has been suggested as a necessarily early event in the development of neoplasia.Execution of the apoptotic cell death process is carried out by caspases, a family of cysteine aspartate proteases. 3,4 During apoptosis, loss of mitochondrial integrity or engagement of death receptors leads to the activation of initiator caspase-9 or -8, respectively. In either case, the initiator caspases cleave and activate effector caspases, including caspase-3 or -7. The cascade of caspase cleavage is regulated by X-linked inhibitor of apoptosis protein (XIAP). XIAP belongs to the IAP family, characterized by containing at least one zinc-binding baculovirus IAP repeat. 5 The only member of the IAP family that potently inhibits caspase activity, XIAP has been demonstrated to directly inhibit caspases-3, -7 and -9, blocking both intrinsic and extrinsic apoptotic signals. 6 Given its role in apoptosis, there has been much interest in understanding the role of XIAP in cancer and evaluating XIAP as a therapeutic target. [7][8][9] XIAP overexpression has been reported in a variety of human ca...

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Immunohistochemical detection of antiapoptotic protein X-linked inhibitor of apoptosis in mammary carcinoma

Cited by 38 publications

References 27 publications

Expression of IAP family proteins and its clinical importance in breast cancer patients

Expression of IAP family proteins and its clinical importance in breast cancer patients

Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism

X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model

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