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Up-regulation of cell cycle arrest protein BTG2 correlates with increased overall survival in breast cancer, as detected by immunohistochemistry using tissue microarray.

Möllerström E, Kovács A, Lövgren K, Nemes S, Delle U, Danielsson A, Parris T, Brennan DJ, Jirström K, Karlsson P, Helou K - BMC Cancer (2010)

Bottom Line: BTG2 expression was demonstrated in a significantly lower proportion of samples from dead patients compared to alive patients, both in overall expression (P = 0.026) and cell membrane specific expression (P = 0.013), whereas neither ADIPOR1, ADORA1 nor CD46 showed differential expression in the two survival groups.Furthermore, a multivariate analysis showed that a model containing BTG2 expression in combination with HER2 and Ki67 expression along with patient age performed better than a model containing the currently used prognostic markers (tumour size, nodal status, HER2 expression, hormone receptor status, histological grade, and patient age).Interestingly, BTG2 has previously been described as a tumour suppressor gene involved in cell cycle arrest and p53 signalling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, Institute of Clinical Sciences, Blå stråket 2, University of Gothenburg, SE-413 45 Göteborg, Sweden. elin.mollerstrom@neuro.gu.se

ABSTRACT

Background: Previous studies have shown that the ADIPOR1, ADORA1, BTG2 and CD46 genes differ significantly between long-term survivors of breast cancer and deceased patients, both in levels of gene expression and DNA copy numbers. The aim of this study was to characterize the expression of the corresponding proteins in breast carcinoma and to determine their correlation with clinical outcome.

Methods: Protein expression was evaluated using immunohistochemistry in an independent breast cancer cohort of 144 samples represented on tissue microarrays. Fisher's exact test was used to analyze the differences in protein expression between dead and alive patients. We used Cox-regression multivariate analysis to assess whether the new markers predict the survival status of the patients better than the currently used markers.

Results: BTG2 expression was demonstrated in a significantly lower proportion of samples from dead patients compared to alive patients, both in overall expression (P = 0.026) and cell membrane specific expression (P = 0.013), whereas neither ADIPOR1, ADORA1 nor CD46 showed differential expression in the two survival groups. Furthermore, a multivariate analysis showed that a model containing BTG2 expression in combination with HER2 and Ki67 expression along with patient age performed better than a model containing the currently used prognostic markers (tumour size, nodal status, HER2 expression, hormone receptor status, histological grade, and patient age). Interestingly, BTG2 has previously been described as a tumour suppressor gene involved in cell cycle arrest and p53 signalling.

Conclusions: We conclude that high-level BTG2 protein expression correlates with prolonged survival in patients with breast carcinoma.

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Sub-cellular location of the BTG2 protein in this study. Brown colour represents BTG2 staining. BTG2 protein immunohistochemistry staining using tissue microarrays show exclusive cell membrane specific expression (A), exclusive cytoplasm expression (B), and both cell membrane and cytoplasm expression of BTG2 in the same sample (C).
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Figure 1: Sub-cellular location of the BTG2 protein in this study. Brown colour represents BTG2 staining. BTG2 protein immunohistochemistry staining using tissue microarrays show exclusive cell membrane specific expression (A), exclusive cytoplasm expression (B), and both cell membrane and cytoplasm expression of BTG2 in the same sample (C).

Mentions: Of the 144 specimens present in the tissue microarray, 136-141 were interpretable for protein expression (Table 3). Excluded samples had few tumour cells, large tissue loss or affluence of necrotic tissue. BTG2 was expressed in both the cytoplasm and the cell membrane (Figure 1). In one sample, BTG2 showed expression in the cytoplasm and the membrane in one area and was expressed in the membrane exclusively in another area (Figure 2). The proportion of BTG2 protein expression was higher in tumours from 5-year overall survivors than among the tumours from deceased patients. The overall expression differed significantly between alive and dead patients (P = 0.026), although there was a stronger association with membrane specific expression (P = 0.013) (Table 3). Kaplan-Meier curves visualize the difference in overall survival between patients with tumours positive versus negative for overall and cell membrane specific BTG2 expression in Figure 3. Moreover, the difference between the curves was significant using the Breslow-Wilcoxon test [12] for both overall BTG2 (P = 0.011) and cell membrane expression (P = 0.015). Cytoplasm or cell membrane expression of BTG2 was observed in 78% of the samples and cell membrane specific expression in 39% of the samples. None of the remaining three analysed proteins (ADORA1, ADORA1 and CD46) showed a statistically significant difference in expression between alive and dead patients in this study (Table 3). The ADIPOR1 protein was expressed in the cytoplasm in 18% of the samples. The majority of the positive samples showed primarily granular staining (Figure 4a). Approximately 24% of the samples were positive for ADORA1 staining, also displaying primarily granular staining in the cytoplasm (Figure 4b). Fourteen percent of the samples expressed CD46 in the cell membrane (Figure 4c).


Up-regulation of cell cycle arrest protein BTG2 correlates with increased overall survival in breast cancer, as detected by immunohistochemistry using tissue microarray.

Möllerström E, Kovács A, Lövgren K, Nemes S, Delle U, Danielsson A, Parris T, Brennan DJ, Jirström K, Karlsson P, Helou K - BMC Cancer (2010)

Sub-cellular location of the BTG2 protein in this study. Brown colour represents BTG2 staining. BTG2 protein immunohistochemistry staining using tissue microarrays show exclusive cell membrane specific expression (A), exclusive cytoplasm expression (B), and both cell membrane and cytoplasm expression of BTG2 in the same sample (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902444&req=5

Figure 1: Sub-cellular location of the BTG2 protein in this study. Brown colour represents BTG2 staining. BTG2 protein immunohistochemistry staining using tissue microarrays show exclusive cell membrane specific expression (A), exclusive cytoplasm expression (B), and both cell membrane and cytoplasm expression of BTG2 in the same sample (C).
Mentions: Of the 144 specimens present in the tissue microarray, 136-141 were interpretable for protein expression (Table 3). Excluded samples had few tumour cells, large tissue loss or affluence of necrotic tissue. BTG2 was expressed in both the cytoplasm and the cell membrane (Figure 1). In one sample, BTG2 showed expression in the cytoplasm and the membrane in one area and was expressed in the membrane exclusively in another area (Figure 2). The proportion of BTG2 protein expression was higher in tumours from 5-year overall survivors than among the tumours from deceased patients. The overall expression differed significantly between alive and dead patients (P = 0.026), although there was a stronger association with membrane specific expression (P = 0.013) (Table 3). Kaplan-Meier curves visualize the difference in overall survival between patients with tumours positive versus negative for overall and cell membrane specific BTG2 expression in Figure 3. Moreover, the difference between the curves was significant using the Breslow-Wilcoxon test [12] for both overall BTG2 (P = 0.011) and cell membrane expression (P = 0.015). Cytoplasm or cell membrane expression of BTG2 was observed in 78% of the samples and cell membrane specific expression in 39% of the samples. None of the remaining three analysed proteins (ADORA1, ADORA1 and CD46) showed a statistically significant difference in expression between alive and dead patients in this study (Table 3). The ADIPOR1 protein was expressed in the cytoplasm in 18% of the samples. The majority of the positive samples showed primarily granular staining (Figure 4a). Approximately 24% of the samples were positive for ADORA1 staining, also displaying primarily granular staining in the cytoplasm (Figure 4b). Fourteen percent of the samples expressed CD46 in the cell membrane (Figure 4c).

Bottom Line: BTG2 expression was demonstrated in a significantly lower proportion of samples from dead patients compared to alive patients, both in overall expression (P = 0.026) and cell membrane specific expression (P = 0.013), whereas neither ADIPOR1, ADORA1 nor CD46 showed differential expression in the two survival groups.Furthermore, a multivariate analysis showed that a model containing BTG2 expression in combination with HER2 and Ki67 expression along with patient age performed better than a model containing the currently used prognostic markers (tumour size, nodal status, HER2 expression, hormone receptor status, histological grade, and patient age).Interestingly, BTG2 has previously been described as a tumour suppressor gene involved in cell cycle arrest and p53 signalling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, Institute of Clinical Sciences, Blå stråket 2, University of Gothenburg, SE-413 45 Göteborg, Sweden. elin.mollerstrom@neuro.gu.se

ABSTRACT

Background: Previous studies have shown that the ADIPOR1, ADORA1, BTG2 and CD46 genes differ significantly between long-term survivors of breast cancer and deceased patients, both in levels of gene expression and DNA copy numbers. The aim of this study was to characterize the expression of the corresponding proteins in breast carcinoma and to determine their correlation with clinical outcome.

Methods: Protein expression was evaluated using immunohistochemistry in an independent breast cancer cohort of 144 samples represented on tissue microarrays. Fisher's exact test was used to analyze the differences in protein expression between dead and alive patients. We used Cox-regression multivariate analysis to assess whether the new markers predict the survival status of the patients better than the currently used markers.

Results: BTG2 expression was demonstrated in a significantly lower proportion of samples from dead patients compared to alive patients, both in overall expression (P = 0.026) and cell membrane specific expression (P = 0.013), whereas neither ADIPOR1, ADORA1 nor CD46 showed differential expression in the two survival groups. Furthermore, a multivariate analysis showed that a model containing BTG2 expression in combination with HER2 and Ki67 expression along with patient age performed better than a model containing the currently used prognostic markers (tumour size, nodal status, HER2 expression, hormone receptor status, histological grade, and patient age). Interestingly, BTG2 has previously been described as a tumour suppressor gene involved in cell cycle arrest and p53 signalling.

Conclusions: We conclude that high-level BTG2 protein expression correlates with prolonged survival in patients with breast carcinoma.

Show MeSH
Related in: MedlinePlus