Limits...
Novel molecular markers of malignancy in histologically normal and benign breast.

Nasir A, Chen DT, Gruidl M, Henderson-Jackson EB, Venkataramu C, McCarthy SM, McBride HL, Harris E, Khakpour N, Yeatman TJ - Patholog Res Int (2011)

Bottom Line: We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA).In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues.Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomic Pathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

ABSTRACT
To detect the molecular changes of malignancy in histologically normal breast (HNB) tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A), minichromosome-maintenance-protein-2 (MCM2) and "budding-uninhibited-by-benzimidazoles-1-homolog-beta" (BUB1B) at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; N = 9) and high-grade molecular abnormality (HNB-HGMA; N = 9). Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC) tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (%) and BUB1B expression as H-scores (0-300). Increasing TOP2A, MCM2, and BUB1B protein expression from HNB-LGMA to HNB-HGMA tissues to IDCs validated our microarray-based molecular classification of HNB tissues by immunohistochemistry. We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA). In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues. Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemical expresssion of TOP2A protein in HNB tissues with low-grade and high-grade molecular abnormalities and in IDCs. There is an obvious trend toward increasing expression from HNB tissues with low-grade molecular abnormality (white bars) to those with high-grade molecular abnormality (gray bars), and the IDCs (black bars), thus providing evidence for cross-platform validation of our original expression profiling data for TOP2A at the protein level. (a) Is the specimen-wise distribution of immunohistochemical expression of TOP2A for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) is the pairwise comparison of TOP2A immunostaining among the three groups. For each comparison (e.g., IDC versus normal), a mean difference with a 95% confidence interval (95% CI) is displayed to examine whether the difference is statistically significant (A 95% CI deviated away from 0 is statistically significant). The adjusted P value for each comparison, based on Tukey method, is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3140260&req=5

fig6: Immunohistochemical expresssion of TOP2A protein in HNB tissues with low-grade and high-grade molecular abnormalities and in IDCs. There is an obvious trend toward increasing expression from HNB tissues with low-grade molecular abnormality (white bars) to those with high-grade molecular abnormality (gray bars), and the IDCs (black bars), thus providing evidence for cross-platform validation of our original expression profiling data for TOP2A at the protein level. (a) Is the specimen-wise distribution of immunohistochemical expression of TOP2A for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) is the pairwise comparison of TOP2A immunostaining among the three groups. For each comparison (e.g., IDC versus normal), a mean difference with a 95% confidence interval (95% CI) is displayed to examine whether the difference is statistically significant (A 95% CI deviated away from 0 is statistically significant). The adjusted P value for each comparison, based on Tukey method, is shown.

Mentions: Expression of TOP2A was nuclear both in the tumor cells (Figure 2(b)) and in the acinar and ductal epithelial cells present in the histologically normal breast tissues with high-grade (Figure 3(b)) and low-grade (Figure 4(b)) molecular abnormality. Mean TOP2A nuclear staining index values for IDCs and histologically normal breast tissues with high-grade and low-grade molecular abnormality were 27, 11, and 2, respectively. Compared to HNB tissues with low-grade molecular abnormality, TOP2A expression in HNB tissues with high-grade molecular abnormality was significantly higher, both in terms of absolute (Table 4) and mean (Table 3, Figure 6) TOP2A expression indices, thus validating our TOP2A gene expression data from frozen to archival histologically normal breast tissues at the protein level.


Novel molecular markers of malignancy in histologically normal and benign breast.

Nasir A, Chen DT, Gruidl M, Henderson-Jackson EB, Venkataramu C, McCarthy SM, McBride HL, Harris E, Khakpour N, Yeatman TJ - Patholog Res Int (2011)

Immunohistochemical expresssion of TOP2A protein in HNB tissues with low-grade and high-grade molecular abnormalities and in IDCs. There is an obvious trend toward increasing expression from HNB tissues with low-grade molecular abnormality (white bars) to those with high-grade molecular abnormality (gray bars), and the IDCs (black bars), thus providing evidence for cross-platform validation of our original expression profiling data for TOP2A at the protein level. (a) Is the specimen-wise distribution of immunohistochemical expression of TOP2A for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) is the pairwise comparison of TOP2A immunostaining among the three groups. For each comparison (e.g., IDC versus normal), a mean difference with a 95% confidence interval (95% CI) is displayed to examine whether the difference is statistically significant (A 95% CI deviated away from 0 is statistically significant). The adjusted P value for each comparison, based on Tukey method, is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140260&req=5

fig6: Immunohistochemical expresssion of TOP2A protein in HNB tissues with low-grade and high-grade molecular abnormalities and in IDCs. There is an obvious trend toward increasing expression from HNB tissues with low-grade molecular abnormality (white bars) to those with high-grade molecular abnormality (gray bars), and the IDCs (black bars), thus providing evidence for cross-platform validation of our original expression profiling data for TOP2A at the protein level. (a) Is the specimen-wise distribution of immunohistochemical expression of TOP2A for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) is the pairwise comparison of TOP2A immunostaining among the three groups. For each comparison (e.g., IDC versus normal), a mean difference with a 95% confidence interval (95% CI) is displayed to examine whether the difference is statistically significant (A 95% CI deviated away from 0 is statistically significant). The adjusted P value for each comparison, based on Tukey method, is shown.
Mentions: Expression of TOP2A was nuclear both in the tumor cells (Figure 2(b)) and in the acinar and ductal epithelial cells present in the histologically normal breast tissues with high-grade (Figure 3(b)) and low-grade (Figure 4(b)) molecular abnormality. Mean TOP2A nuclear staining index values for IDCs and histologically normal breast tissues with high-grade and low-grade molecular abnormality were 27, 11, and 2, respectively. Compared to HNB tissues with low-grade molecular abnormality, TOP2A expression in HNB tissues with high-grade molecular abnormality was significantly higher, both in terms of absolute (Table 4) and mean (Table 3, Figure 6) TOP2A expression indices, thus validating our TOP2A gene expression data from frozen to archival histologically normal breast tissues at the protein level.

Bottom Line: We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA).In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues.Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomic Pathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

ABSTRACT
To detect the molecular changes of malignancy in histologically normal breast (HNB) tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A), minichromosome-maintenance-protein-2 (MCM2) and "budding-uninhibited-by-benzimidazoles-1-homolog-beta" (BUB1B) at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; N = 9) and high-grade molecular abnormality (HNB-HGMA; N = 9). Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC) tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (%) and BUB1B expression as H-scores (0-300). Increasing TOP2A, MCM2, and BUB1B protein expression from HNB-LGMA to HNB-HGMA tissues to IDCs validated our microarray-based molecular classification of HNB tissues by immunohistochemistry. We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA). In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues. Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers.

No MeSH data available.


Related in: MedlinePlus