Skip to main content
Top
Published in: Medical Oncology 8/2014

01-08-2014 | Short Communication

Positive immunohistochemical expression of bcl-2 in hormone-independent breast carcinomas is associated with a greater lymph node involvement and poor outcome

Authors: Álvaro Ruibal, Pablo Aguiar, María Carmen Del Río, Primitiva Menéndez, José Ignacio Arias, Michel Herranz

Published in: Medical Oncology | Issue 8/2014

Login to get access

Abstract

To study the immunohistochemical expression of bcl-2 in patients with hormone-independent breast infiltrating ductal carcinomas (IDC) and its possible association with other clinico-biological parameters and outcome. Our study group included 72 females with hormone-independent (ER and PgR negative) infiltrating ductal breast carcinomas. Age, tumor size, axillary lymph node involvement (N), distant metastasis and histological grade, as well as the immunohistochemical expression of Ki67, p53 and androgen receptor (AR), were analyzed. We follow up 57 patients during a period of time ranged between 20 and 193 months (80.2 ± 58.3; median 78 months). Of all IDCs included in our study, 18 were ER-/PgR-/bcl-2+ and 54 ER-/PgR-/bcl-2−. The percentages of slightly bcl-2-positive (+) and bcl-2-strong positive (++) cases were 25 and 19 %, respectively, values lower than those observed in ER+/PgR+ tumors (79.3 and 86.8 %, respectively). Breast IDC with positivity (+) for bcl-2 showed, exclusively, greater lymph node involvement higher than 3 nodes (N+ >3) (p 0.021) and a great number of deaths due to the tumor (p 0.011). Same results were obtained when we compared bcl-2-negative and bcl-2-strong positive (++) subgroups. Our results led us to consider that the positive (+ or ++) immunohistochemical expression of bcl-2 in hormone-independent (ER and PgR negative) breast carcinomas is associated with greater axillary lymph node involvement and a greater number of deaths in the follow-up, being these data opposite to that observed in hormone-dependent tumors.
Literature
1.
go back to reference Abdel-Fatah TMA, Perry C, Dixkinson P, Ball G, Moseley P, Madhusudan S, Elli IO, et al. Bcl-2 is an independent prognostic marker of triple negative breast cancer (TNBC) and predicts response to anthracycline combination (ATC) chemotherapy (CT) in adjuvant and neoadjuvant settings. Ann Oncol. 2013;24:2801–7.PubMedCrossRef Abdel-Fatah TMA, Perry C, Dixkinson P, Ball G, Moseley P, Madhusudan S, Elli IO, et al. Bcl-2 is an independent prognostic marker of triple negative breast cancer (TNBC) and predicts response to anthracycline combination (ATC) chemotherapy (CT) in adjuvant and neoadjuvant settings. Ann Oncol. 2013;24:2801–7.PubMedCrossRef
2.
go back to reference Azad N, Iyer A, Vallyathan V, Wang L, Castranova V, Stehlik C, Rpjanasakuul Y. Role of oxidative(nitrosative stress –mediated Bcl-2 regulation in apoptosis and malignant transformation. Ann NY Acad Sci. 2010;1203:1–6.PubMedCrossRef Azad N, Iyer A, Vallyathan V, Wang L, Castranova V, Stehlik C, Rpjanasakuul Y. Role of oxidative(nitrosative stress –mediated Bcl-2 regulation in apoptosis and malignant transformation. Ann NY Acad Sci. 2010;1203:1–6.PubMedCrossRef
3.
go back to reference Basu A, Haldar S. The relationship between bcl-2, bax and p53: consequences for cell cycle progression and cell death. Mol Hum Reproduct. 1998;4:1099–109.CrossRef Basu A, Haldar S. The relationship between bcl-2, bax and p53: consequences for cell cycle progression and cell death. Mol Hum Reproduct. 1998;4:1099–109.CrossRef
4.
go back to reference Callagy GM, Webber MJ, Pharoah PD, Caldas C. Meta-analysis confirms BCL-2 is an independent prognostic marker in breast cancer. BMC Cancer. 2008;8:153.PubMedCentralPubMedCrossRef Callagy GM, Webber MJ, Pharoah PD, Caldas C. Meta-analysis confirms BCL-2 is an independent prognostic marker in breast cancer. BMC Cancer. 2008;8:153.PubMedCentralPubMedCrossRef
5.
go back to reference Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, et al. Bcl-2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer. 2010;103:668–75.PubMedCentralPubMedCrossRef Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, et al. Bcl-2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer. 2010;103:668–75.PubMedCentralPubMedCrossRef
6.
go back to reference Dueñas-González A, Abad-Hernández MM, Cruz-Hernández JJ, González-Sarmiento R. Analysis of bcl-2 in sporadic breast carcinoma. Cancer. 1997;80:2100–8.PubMedCrossRef Dueñas-González A, Abad-Hernández MM, Cruz-Hernández JJ, González-Sarmiento R. Analysis of bcl-2 in sporadic breast carcinoma. Cancer. 1997;80:2100–8.PubMedCrossRef
7.
go back to reference Haldar S, Negrini M, Monne M, Sabbioni S, Croce CM. Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 1994;54:2095–209.PubMed Haldar S, Negrini M, Monne M, Sabbioni S, Croce CM. Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 1994;54:2095–209.PubMed
8.
go back to reference Hwang KT, Woo JW, Shin HC, Kim HS, Ahn SK, Moon HG, et al. Prognostic influence of Bcl-2 expression in breast cancer. Int J Cancer. 2012;131:1109–19.CrossRef Hwang KT, Woo JW, Shin HC, Kim HS, Ahn SK, Moon HG, et al. Prognostic influence of Bcl-2 expression in breast cancer. Int J Cancer. 2012;131:1109–19.CrossRef
9.
go back to reference Hyndi M, Sorensen FB, Knudsen H, Alsner J, Overgaard M, Nielsen HM, et al. Impact of bcl-2 and p53 on postmastectomy radiotherapy response in high-risk breast cancer. A subgroup analysis of DBCG82 b&c. Acta Oncol. 2008;47:608–17.CrossRef Hyndi M, Sorensen FB, Knudsen H, Alsner J, Overgaard M, Nielsen HM, et al. Impact of bcl-2 and p53 on postmastectomy radiotherapy response in high-risk breast cancer. A subgroup analysis of DBCG82 b&c. Acta Oncol. 2008;47:608–17.CrossRef
10.
go back to reference Krajewski S, Blomqvist C, Franssila K, Krajewska M, Wasenius VM, Niskanen E, et al. Reduced expression of proapoptotic gene bax is associated with poor responde and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res. 1995;55:4471–8.PubMed Krajewski S, Blomqvist C, Franssila K, Krajewska M, Wasenius VM, Niskanen E, et al. Reduced expression of proapoptotic gene bax is associated with poor responde and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res. 1995;55:4471–8.PubMed
11.
go back to reference Lacle MM, van der Pol C, Witkamp A, van der Wall E, van Diest PJ. Prognostic value of mitotic index and bcl-2 expression in male breast cancer. PLoS ONE. 2013;8:e60138.PubMedCentralPubMedCrossRef Lacle MM, van der Pol C, Witkamp A, van der Wall E, van Diest PJ. Prognostic value of mitotic index and bcl-2 expression in male breast cancer. PLoS ONE. 2013;8:e60138.PubMedCentralPubMedCrossRef
12.
go back to reference Li L, Backer J, Annisa S, Wong SK, Schwanke EL, Stewart BG, et al. Bcl-2 expression decreases cadherin-mediated cell–cell adhesion. J Cell Sci. 2003;116:3687–700.PubMedCrossRef Li L, Backer J, Annisa S, Wong SK, Schwanke EL, Stewart BG, et al. Bcl-2 expression decreases cadherin-mediated cell–cell adhesion. J Cell Sci. 2003;116:3687–700.PubMedCrossRef
13.
go back to reference Luna-Moré S, Weil B, Bautista D, Garrido E, Florez P, Martínez C. Bcl-2 protein in normal, hyperplastic and neoplastic breast tissues. A metabolite of the putative stem-cell subpopulation of the mammary gland. Histoll Histopathol. 2004;19:457–63. Luna-Moré S, Weil B, Bautista D, Garrido E, Florez P, Martínez C. Bcl-2 protein in normal, hyperplastic and neoplastic breast tissues. A metabolite of the putative stem-cell subpopulation of the mammary gland. Histoll Histopathol. 2004;19:457–63.
14.
go back to reference Martínez Arribas F, Alvarez T, Del Val G, Martín Garabato E, Nuñez Villar MJ, Lucas R, et al. Bcl-2 expression in breast cancer: a comparative study at the mRNA and protein level. Anticancer Res. 2007;27:219–22.PubMed Martínez Arribas F, Alvarez T, Del Val G, Martín Garabato E, Nuñez Villar MJ, Lucas R, et al. Bcl-2 expression in breast cancer: a comparative study at the mRNA and protein level. Anticancer Res. 2007;27:219–22.PubMed
15.
go back to reference Naumovski L, Cleary MI. The p53-binding protein 53BP2 also interacts with Bcl-2 and impedes cell cycle progression at G2/M. Mol Cell Biol. 1996;16:3884–92.PubMedCentralPubMed Naumovski L, Cleary MI. The p53-binding protein 53BP2 also interacts with Bcl-2 and impedes cell cycle progression at G2/M. Mol Cell Biol. 1996;16:3884–92.PubMedCentralPubMed
16.
go back to reference Oakes SR, Vaillant F, Lim E, Lee L, Breslin K, Feleppa F, et al. Sensitization of BCl-2 expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci USA. 2012;109:2766–71.PubMedCentralPubMedCrossRef Oakes SR, Vaillant F, Lim E, Lee L, Breslin K, Feleppa F, et al. Sensitization of BCl-2 expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci USA. 2012;109:2766–71.PubMedCentralPubMedCrossRef
17.
go back to reference Saxena N, Katiyar SP, Liu Y, Grover A, Gao R, Sundar D, Kaul SC, Wandhwa R. Molecular interactions of Bcl-2 and Bcl-xL with mortalin: identification and functional characterization. Biosci Rep. 2013;33(5):e00073.PubMedCentralPubMedCrossRef Saxena N, Katiyar SP, Liu Y, Grover A, Gao R, Sundar D, Kaul SC, Wandhwa R. Molecular interactions of Bcl-2 and Bcl-xL with mortalin: identification and functional characterization. Biosci Rep. 2013;33(5):e00073.PubMedCentralPubMedCrossRef
18.
go back to reference Silvestrini R, Benini E, Veneroni S, Daidone MG, Tomasic G, Squicciarini P, et al. p53 and bcl-2 expression correlates with clinical outcome in a series of node positive breast cancer patients. J Clin Oncol. 1996;14:1604–10.PubMed Silvestrini R, Benini E, Veneroni S, Daidone MG, Tomasic G, Squicciarini P, et al. p53 and bcl-2 expression correlates with clinical outcome in a series of node positive breast cancer patients. J Clin Oncol. 1996;14:1604–10.PubMed
19.
go back to reference Stone A, Cowley MJ, Valdes-Mora F, McCloy RA, Segio CM, Gallego-Ortega D, et al. Bcl-2 hypermethylation is a potential biomarker of sensitivity to antimitotic chemotherapy in endocrine-resistant breast cancer. Mol Cancer Ther. 2013;12:1874–85.PubMedCrossRef Stone A, Cowley MJ, Valdes-Mora F, McCloy RA, Segio CM, Gallego-Ortega D, et al. Bcl-2 hypermethylation is a potential biomarker of sensitivity to antimitotic chemotherapy in endocrine-resistant breast cancer. Mol Cancer Ther. 2013;12:1874–85.PubMedCrossRef
20.
go back to reference Tawfik K, Kimler BF, Davis MK, Fan F, Tawfik O. Prognostic significance of Bcl-2 in invasive mammary carcinomas: a comparative clinicopathologic study between “triple-negative” and non-”triple-negative” tumors. Hum Pathol. 2012;43:23–30.PubMedCrossRef Tawfik K, Kimler BF, Davis MK, Fan F, Tawfik O. Prognostic significance of Bcl-2 in invasive mammary carcinomas: a comparative clinicopathologic study between “triple-negative” and non-”triple-negative” tumors. Hum Pathol. 2012;43:23–30.PubMedCrossRef
21.
go back to reference Teixeira C, Reed JC, Partt MA. Estrogen promotes chemotherapeutic drug resistance by a mechanism involving bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res. 1995;55:3902–7.PubMed Teixeira C, Reed JC, Partt MA. Estrogen promotes chemotherapeutic drug resistance by a mechanism involving bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res. 1995;55:3902–7.PubMed
22.
go back to reference Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein Ch, et al. Rp53, but not tumor-derived mutants, bind to bcl-2 via DNA binding domain and induces mitochondrial permeabilization. J Biol Chem. 2006;281:8600–6.PubMedCrossRef Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein Ch, et al. Rp53, but not tumor-derived mutants, bind to bcl-2 via DNA binding domain and induces mitochondrial permeabilization. J Biol Chem. 2006;281:8600–6.PubMedCrossRef
23.
go back to reference Wu Y, Mehew JW, Heckman CA, Arcinas M, Boxer LM. Negative regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene. 2001;20:240–51.PubMedCrossRef Wu Y, Mehew JW, Heckman CA, Arcinas M, Boxer LM. Negative regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene. 2001;20:240–51.PubMedCrossRef
Metadata
Title
Positive immunohistochemical expression of bcl-2 in hormone-independent breast carcinomas is associated with a greater lymph node involvement and poor outcome
Authors
Álvaro Ruibal
Pablo Aguiar
María Carmen Del Río
Primitiva Menéndez
José Ignacio Arias
Michel Herranz
Publication date
01-08-2014
Publisher
Springer US
Published in
Medical Oncology / Issue 8/2014
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-014-0105-6

Other articles of this Issue 8/2014

Medical Oncology 8/2014 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.