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Article

Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy

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Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
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Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
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Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 13009 Marseille, France
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Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
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Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France
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GZA Hospitals Sint-Augustinus, 2018 Antwerp, Belgium
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Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA
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Department of Pathology and Laboratory Medicine, East Carolina University Brody School of Medicine, Greenville, NC 27858, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Tommaso Susini
Cancers 2021, 13(11), 2807; https://doi.org/10.3390/cancers13112807
Received: 16 April 2021 / Revised: 28 May 2021 / Accepted: 29 May 2021 / Published: 4 June 2021
(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)
The X-linked inhibitor of apoptosis protein (XIAP) is considered the most potent inhibitor of cell death, and it is well established that XIAP promotes resistance to chemotherapy, radiation, and anti-cancer immune responses. This study evaluates the correlations between XIAP expression and clinicopathological features, including disease-free survival (DFS) and pathological complete response (pCR) to chemotherapy, in more than 2300 invasive primary breast cancer samples. We found a significant association of XIAP expression with younger patients’ age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, and PAM50 luminal B subtype. Analysis of molecular subtypes revealed a stronger prognostic value in HR+/HER2− tumors. Higher XIAP expression was associated with shorter DFS and lower pCR rate to chemotherapy in both uni- and multivariate analyses. All these correlations were observed at both the RNA and protein level, indicating the potential of XIAP as a promising therapeutic target in primary invasive breast cancer.
XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for XIAP mRNA (n = 2341) and protein (n = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. XIAP mRNA expression was heterogeneous across samples and significantly associated with younger patients’ age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2− status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2− but not in the TN subtype. Finally, XIAP mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP. View Full-Text
Keywords: anthracycline; apoptosis; cell death; HER2; luminal B; metastasis; pCR; proteomics; taxanes; TN; XIAP anthracycline; apoptosis; cell death; HER2; luminal B; metastasis; pCR; proteomics; taxanes; TN; XIAP
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MDPI and ACS Style

Devi, G.R.; Finetti, P.; Morse, M.A.; Lee, S.; de Nonneville, A.; Van Laere, S.; Troy, J.; Geradts, J.; McCall, S.; Bertucci, F. Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy. Cancers 2021, 13, 2807. https://doi.org/10.3390/cancers13112807

AMA Style

Devi GR, Finetti P, Morse MA, Lee S, de Nonneville A, Van Laere S, Troy J, Geradts J, McCall S, Bertucci F. Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy. Cancers. 2021; 13(11):2807. https://doi.org/10.3390/cancers13112807

Chicago/Turabian Style

Devi, Gayathri R., Pascal Finetti, Michael A. Morse, Seayoung Lee, Alexandre de Nonneville, Steven Van Laere, Jesse Troy, Joseph Geradts, Shannon McCall, and Francois Bertucci. 2021. "Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy" Cancers 13, no. 11: 2807. https://doi.org/10.3390/cancers13112807

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