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Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients

Transcriptional activation by estrogen receptor (ER) is a key step to breast oncogenesis. Given previous findings that ADA3 is a critical component of HAT complexes that regulate ER function and evidence that overexpression of other ER coactivators such as SRC-3 is associated with clinical outcomes...

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Autores principales: Mirza, Sameer, Rakha, Emad A., Alshareeda, Alaa, Mohibi, Shakur, Zhao, Xiangshan, Katafiasz, Bryan J., Wang, Jun, Gurumurthy, Channabasavaiah Basavaraju, Bele, Aditya, Ellis, Ian O., Green, Andrew R., Band, Hamid, Band, Vimla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552361/
https://www.ncbi.nlm.nih.gov/pubmed/23288344
http://dx.doi.org/10.1007/s10549-012-2363-3
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author Mirza, Sameer
Rakha, Emad A.
Alshareeda, Alaa
Mohibi, Shakur
Zhao, Xiangshan
Katafiasz, Bryan J.
Wang, Jun
Gurumurthy, Channabasavaiah Basavaraju
Bele, Aditya
Ellis, Ian O.
Green, Andrew R.
Band, Hamid
Band, Vimla
author_facet Mirza, Sameer
Rakha, Emad A.
Alshareeda, Alaa
Mohibi, Shakur
Zhao, Xiangshan
Katafiasz, Bryan J.
Wang, Jun
Gurumurthy, Channabasavaiah Basavaraju
Bele, Aditya
Ellis, Ian O.
Green, Andrew R.
Band, Hamid
Band, Vimla
author_sort Mirza, Sameer
collection PubMed
description Transcriptional activation by estrogen receptor (ER) is a key step to breast oncogenesis. Given previous findings that ADA3 is a critical component of HAT complexes that regulate ER function and evidence that overexpression of other ER coactivators such as SRC-3 is associated with clinical outcomes in breast cancer, the current study was designed to assess the potential significance of ADA3 expression/localization in human breast cancer patients. In this study, we analyzed ADA3 expression in breast cancer tissue specimens and assessed the correlation of ADA3 staining with cancer progression and patient outcome. Tissue microarrays prepared from large series of breast cancer patients with long-term follow-ups were stained with anti-ADA3 monoclonal antibody using immunohistochemistry. Samples were analyzed for ADA3 expression followed by correlation with various clinicopathological parameters and patients’ outcomes. We report that breast cancer specimens show predominant nuclear, cytoplasmic, or mixed nuclear + cytoplasmic ADA3 staining patterns. Predominant nuclear ADA3 staining correlated with ER+ status. While predominant cytoplasmic ADA3 staining negatively correlated with ER+ status, but positively correlated with ErbB2, EGFR, and Ki67. Furthermore, a positive correlation of cytoplasmic ADA3 was observed with higher histological grade, mitotic counts, Nottingham Prognostic Index, and positive vascular invasion. Patients with nuclear ADA3 and ER positivity have better breast cancer specific survival and distant metastasis free survival. Significantly, cytoplasmic expression of ADA3 showed a strong positive association with reduced BCSS and DMFS in ErbB2+/EGFR+ patients. Although in multivariate analyses ADA3 expression was not an independent marker of survival, predominant nuclear ADA3 staining in breast cancer tissues correlates with ER+ expression and together serves as a marker of good prognosis, whereas predominant cytoplasmic ADA3 expression correlates with ErbB2+/EGFR+ expression and together is a marker of poor prognosis. Thus, ADA3 cytoplasmic localization together with ErbB2+/EGFR+ status may serve as better prognostic marker than individual proteins to predict survival of patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-012-2363-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-35523612013-01-24 Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients Mirza, Sameer Rakha, Emad A. Alshareeda, Alaa Mohibi, Shakur Zhao, Xiangshan Katafiasz, Bryan J. Wang, Jun Gurumurthy, Channabasavaiah Basavaraju Bele, Aditya Ellis, Ian O. Green, Andrew R. Band, Hamid Band, Vimla Breast Cancer Res Treat Preclinical Study Transcriptional activation by estrogen receptor (ER) is a key step to breast oncogenesis. Given previous findings that ADA3 is a critical component of HAT complexes that regulate ER function and evidence that overexpression of other ER coactivators such as SRC-3 is associated with clinical outcomes in breast cancer, the current study was designed to assess the potential significance of ADA3 expression/localization in human breast cancer patients. In this study, we analyzed ADA3 expression in breast cancer tissue specimens and assessed the correlation of ADA3 staining with cancer progression and patient outcome. Tissue microarrays prepared from large series of breast cancer patients with long-term follow-ups were stained with anti-ADA3 monoclonal antibody using immunohistochemistry. Samples were analyzed for ADA3 expression followed by correlation with various clinicopathological parameters and patients’ outcomes. We report that breast cancer specimens show predominant nuclear, cytoplasmic, or mixed nuclear + cytoplasmic ADA3 staining patterns. Predominant nuclear ADA3 staining correlated with ER+ status. While predominant cytoplasmic ADA3 staining negatively correlated with ER+ status, but positively correlated with ErbB2, EGFR, and Ki67. Furthermore, a positive correlation of cytoplasmic ADA3 was observed with higher histological grade, mitotic counts, Nottingham Prognostic Index, and positive vascular invasion. Patients with nuclear ADA3 and ER positivity have better breast cancer specific survival and distant metastasis free survival. Significantly, cytoplasmic expression of ADA3 showed a strong positive association with reduced BCSS and DMFS in ErbB2+/EGFR+ patients. Although in multivariate analyses ADA3 expression was not an independent marker of survival, predominant nuclear ADA3 staining in breast cancer tissues correlates with ER+ expression and together serves as a marker of good prognosis, whereas predominant cytoplasmic ADA3 expression correlates with ErbB2+/EGFR+ expression and together is a marker of poor prognosis. Thus, ADA3 cytoplasmic localization together with ErbB2+/EGFR+ status may serve as better prognostic marker than individual proteins to predict survival of patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-012-2363-3) contains supplementary material, which is available to authorized users. Springer US 2013-01-04 2013 /pmc/articles/PMC3552361/ /pubmed/23288344 http://dx.doi.org/10.1007/s10549-012-2363-3 Text en © The Author(s) 2013 https://creativecommons.org/licenses/by-nc/2.5/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Preclinical Study
Mirza, Sameer
Rakha, Emad A.
Alshareeda, Alaa
Mohibi, Shakur
Zhao, Xiangshan
Katafiasz, Bryan J.
Wang, Jun
Gurumurthy, Channabasavaiah Basavaraju
Bele, Aditya
Ellis, Ian O.
Green, Andrew R.
Band, Hamid
Band, Vimla
Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients
title Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients
title_full Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients
title_fullStr Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients
title_full_unstemmed Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients
title_short Cytoplasmic localization of alteration/deficiency in activation 3 (ADA3) predicts poor clinical outcome in breast cancer patients
title_sort cytoplasmic localization of alteration/deficiency in activation 3 (ada3) predicts poor clinical outcome in breast cancer patients
topic Preclinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552361/
https://www.ncbi.nlm.nih.gov/pubmed/23288344
http://dx.doi.org/10.1007/s10549-012-2363-3
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