Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer - PubMed (original) (raw)

Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer

Yasmine Nadler et al. Breast Cancer Res. 2008.

Abstract

Introduction: Bcl-2 antanogene-1 (Bag-1) binds the anti-apoptotic mediator Bcl-2, and enhances its activity. Bcl-2 and Bag-1 are associated with chemotherapy resistance in cancer cells. Drugs that target Bcl-2 are currently in clinical development. The purpose of the present study was to examine expression patterns of Bag-1 in a large cohort of breast tumors and to assess the association with Bcl-2, estrogen receptor, progesterone receptor and Her2/neu, and other clinical/pathological variables.

Methods: Tissue microarrays containing primary specimens from 638 patients with 10-year follow-up were employed, and the expression of Bag-1, Bcl-2, estrogen receptor, progesterone receptor and Her2/neu was assessed using our automated quantitative analysis method. We used cytokeratin to define pixels as breast cancer (tumor mask) within the array spot, and we measured biomarker expression within the mask using Cy5 conjugated antibodies.

Results: High Bcl-2 expression was associated with improved survival in the entire cohort and in the node-positive subset (P = 0.008 and P = 0.002, respectively). High Bag-1 expression was associated with improved survival in the node-positive subset (P = 0.006). On multivariable analysis, neither Bcl-2 nor Bag-1 retained their independence as prognostic markers. Strong associations were found between Bag-1, Bcl-2, estrogen receptor and progesterone receptor.

Conclusion: Bag-1 and Bcl-2 expression in breast tumors is associated with improved outcome and steroid receptor positivity. Evaluation of Bcl-2 and Bag-1 expression in breast cancer may identify a subset of patients with a favorable prognosis, who might not benefit from chemotherapy or who might benefit from Bcl-2 targeting agents in addition to antihormonal therapy.

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Figures

Figure 1

Figure 1

Principal component analysis and biplot. Projection of five-dimensional patient biomarker profiles with no missing data (439 instances) and the 439-dimensional biomarkers profiles onto the two leading principal components of a matrix consisting of expression profiles of Her2/neu, estrogen receptor (ER), progesterone receptor (PR), Bcl-2 and Bcl-2 antanogene-1 (Bag-1) present in all 439 samples. Each patient is represented by a distinct symbol (•, alive at 10 years; ×, dead at 10 years). The accumulated variation captured by the first and second principal components is 92% of the total variation. Overlaying a two-dimensional scatter plot representing the projection of the biomarkers (formula image) onto the first and second principal components on top of the two-dimensional patient scatter plot representing the projection of their five-dimensional biomarker profiles onto the two leading principal components forms a biplot. The biplot can be used to read the approximated transformed expression levels.

Figure 2

Figure 2

Expression of Bcl-2 antanogene-1 isoforms and Bcl-2. Expression of Bcl-2 antanogene-1 (Bag-1) isoforms and Bcl-2, using β-actin as a loading control in a panel of breast cancer cell lines.

Figure 3

Figure 3

Regression plot for scores from breast cancer arrays stained for Bcl-2 and Bcl-2 antanogene-1. Regression plot for scores from the two breast cancer arrays stained for (a) Bcl-2 and (b) Bcl-2 antanogene-1 (Bag-1). AQUA, automated quantitative analysis.

Figure 4

Figure 4

Immunoflourescent staining of Bcl-2 and Bcl-2 antanogene-1 in breast tumor tissue. (a) Cytoplasmic Bcl-2, (b) cytoplasmic and nuclear Bcl-2 antanogene-1 (Bag-1) and (c) nuclear Bag-1 staining in a breast cancer histospot – using cytokeratin to the define tumor mask, using 4',6-diamidino-2-phenylindole to define the nuclear compartment, and using Cy5 for identifying the target (Bcl-2 and Bag-1).

Figure 5

Figure 5

Kaplan–Meier survival curves for Bcl-2 and Bcl-2 antanogene-1. Kaplan–Meier survival curves for Bcl-2 and Bcl-2 antanogene-1 (Bag-1) automated quantitative analysis scores dichotomized by the median score for (a) the entire cohort of patients, (b) node-negative patients, and (c) node-positive patients.

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