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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 expression of BUB1B 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 BUB1B at the protein level. (a) Is the specimen-wise distribution of immuno-histochemical expression of BUB1B for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) Is the pairwise comparison of BUB1B immunostaining among the three groups. The adjusted P value for each comparison, based on Tukey method, is shown on (b).
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fig7: Immunohistochemical expression of BUB1B 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 BUB1B at the protein level. (a) Is the specimen-wise distribution of immuno-histochemical expression of BUB1B for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) Is the pairwise comparison of BUB1B immunostaining among the three groups. The adjusted P value for each comparison, based on Tukey method, is shown on (b).

Mentions: MCM2 protein expression in IDCs and histologically normal breast tissues with high-grade and low-grade molecular abnormality on microarray Expression of MCM2 was nuclear both in the IDC cells (Figure 2(c)) and in the acinar and ductal epithelial cells present in the histologically normal breast tissues with high-grade (Figure 3(c)) and low-grade (Figure 4(c)) molecular abnormality. Mean MCM2 staining indexes for IDCs and histologically normal breast tissues with high-grade and low-grade molecular abnormality on microarray were 47, 20, and 4, respectively, showing higher immunohistochemical expression of MCM2 in the HNB tissues with high-grade molecular abnormalities compared to the HNB tissues with low-grade molecular abnormality (Table 4, Figure 7), thus validating the same trend as was evident in our gene expression data. While the majority of cases in HNB tissues with low-grade molecular abnormality had MCM2 index of 1-2%, 2 of the cases (Case #s 9 and 14) (Table 4) had higher MCM2 indices (12% and 8%, resp.), closer to the MCM2 index of some of the HNB tissues with high-grade molecular abnormality, suggesting that there may be a degree of heterogeneity in the expression of MCM2 protein in HNB tissues.


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 expression of BUB1B 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 BUB1B at the protein level. (a) Is the specimen-wise distribution of immuno-histochemical expression of BUB1B for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) Is the pairwise comparison of BUB1B immunostaining among the three groups. The adjusted P value for each comparison, based on Tukey method, is shown on (b).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Immunohistochemical expression of BUB1B 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 BUB1B at the protein level. (a) Is the specimen-wise distribution of immuno-histochemical expression of BUB1B for the HNB tissues with low-grade and high-grade molecular abnormality and IDC groups. (b) Is the pairwise comparison of BUB1B immunostaining among the three groups. The adjusted P value for each comparison, based on Tukey method, is shown on (b).
Mentions: MCM2 protein expression in IDCs and histologically normal breast tissues with high-grade and low-grade molecular abnormality on microarray Expression of MCM2 was nuclear both in the IDC cells (Figure 2(c)) and in the acinar and ductal epithelial cells present in the histologically normal breast tissues with high-grade (Figure 3(c)) and low-grade (Figure 4(c)) molecular abnormality. Mean MCM2 staining indexes for IDCs and histologically normal breast tissues with high-grade and low-grade molecular abnormality on microarray were 47, 20, and 4, respectively, showing higher immunohistochemical expression of MCM2 in the HNB tissues with high-grade molecular abnormalities compared to the HNB tissues with low-grade molecular abnormality (Table 4, Figure 7), thus validating the same trend as was evident in our gene expression data. While the majority of cases in HNB tissues with low-grade molecular abnormality had MCM2 index of 1-2%, 2 of the cases (Case #s 9 and 14) (Table 4) had higher MCM2 indices (12% and 8%, resp.), closer to the MCM2 index of some of the HNB tissues with high-grade molecular abnormality, suggesting that there may be a degree of heterogeneity in the expression of MCM2 protein in HNB tissues.

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