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Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease.

Bluff JE, Menakuru SR, Cross SS, Higham SE, Balasubramanian SP, Brown NJ, Reed MW, Staton CA - Br. J. Cancer (2009)

Bottom Line: In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005).Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05).These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.

View Article: PubMed Central - PubMed

Affiliation: Microcirculation Research Group, Academic Unit of Surgical Oncology, University of Sheffield Medical School, Sheffield, South Yorkshire, UK.

ABSTRACT

Background: The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown.

Methods: Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens.

Results: Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P<0.005), and between in situ and invasive carcinomas (P<0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005). Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05). Moreover, HIF-1alpha was expressed by 60-75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (P<0.005) and invasive tumour cells (P<0.01).

Conclusions: These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.

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Immunohistochemical staining for HIF-1α, VEGF and TF. (A) Nuclear HIF-1α staining in the ductal epithelial cells of an ADH case and (B) tumour cells of an invasive cancer. (C) Weak expression of VEGF in normal breast epithelium (score=1), (D) strong expression in florid usual ductal hyperplasia (score=2/3) and (E) strong staining localised to tumour cells within invasive breast carcinomas (score=3). (F) VEGF expression in ECs in normal breast tissue. (G) Tumour cells expressed TF in approximately 55% of invasive breast cancer specimens. (H) TF was expressed in ECs associated with benign hyperplastic tissue (arrow). (I) Putative macrophages expressing TF associated with areas of DCIS (arrows). (J) TF expressed in vessel containing thrombosis (arrow). Photographs A–E and G were taken at × 20 magnification and all others at × 40 magnification.
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fig2: Immunohistochemical staining for HIF-1α, VEGF and TF. (A) Nuclear HIF-1α staining in the ductal epithelial cells of an ADH case and (B) tumour cells of an invasive cancer. (C) Weak expression of VEGF in normal breast epithelium (score=1), (D) strong expression in florid usual ductal hyperplasia (score=2/3) and (E) strong staining localised to tumour cells within invasive breast carcinomas (score=3). (F) VEGF expression in ECs in normal breast tissue. (G) Tumour cells expressed TF in approximately 55% of invasive breast cancer specimens. (H) TF was expressed in ECs associated with benign hyperplastic tissue (arrow). (I) Putative macrophages expressing TF associated with areas of DCIS (arrows). (J) TF expressed in vessel containing thrombosis (arrow). Photographs A–E and G were taken at × 20 magnification and all others at × 40 magnification.

Mentions: Hypoxia-inducible factor-1α protein was not expressed in normal breast tissue, but was expressed in the nuclei of ductal epithelial cells in 65–75% of hyperplastic breast/in situ cancers (Figures 2A and 3A) and in over 90% of invasive cancers (Figures 2B and 3A). There was a moderate correlation between HIF-1α expression and MVD (Spearman's rho correlation coefficient=0.502, P=0.001) and proliferating ECs (Spearman's rho correlation coefficient=0.301, P=0.001). The correlation coefficients for inter- and intraobserver error scores for HIF-1α assessment were 0.88 and 0.91, respectively, showing a high level of agreement.


Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease.

Bluff JE, Menakuru SR, Cross SS, Higham SE, Balasubramanian SP, Brown NJ, Reed MW, Staton CA - Br. J. Cancer (2009)

Immunohistochemical staining for HIF-1α, VEGF and TF. (A) Nuclear HIF-1α staining in the ductal epithelial cells of an ADH case and (B) tumour cells of an invasive cancer. (C) Weak expression of VEGF in normal breast epithelium (score=1), (D) strong expression in florid usual ductal hyperplasia (score=2/3) and (E) strong staining localised to tumour cells within invasive breast carcinomas (score=3). (F) VEGF expression in ECs in normal breast tissue. (G) Tumour cells expressed TF in approximately 55% of invasive breast cancer specimens. (H) TF was expressed in ECs associated with benign hyperplastic tissue (arrow). (I) Putative macrophages expressing TF associated with areas of DCIS (arrows). (J) TF expressed in vessel containing thrombosis (arrow). Photographs A–E and G were taken at × 20 magnification and all others at × 40 magnification.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2736809&req=5

fig2: Immunohistochemical staining for HIF-1α, VEGF and TF. (A) Nuclear HIF-1α staining in the ductal epithelial cells of an ADH case and (B) tumour cells of an invasive cancer. (C) Weak expression of VEGF in normal breast epithelium (score=1), (D) strong expression in florid usual ductal hyperplasia (score=2/3) and (E) strong staining localised to tumour cells within invasive breast carcinomas (score=3). (F) VEGF expression in ECs in normal breast tissue. (G) Tumour cells expressed TF in approximately 55% of invasive breast cancer specimens. (H) TF was expressed in ECs associated with benign hyperplastic tissue (arrow). (I) Putative macrophages expressing TF associated with areas of DCIS (arrows). (J) TF expressed in vessel containing thrombosis (arrow). Photographs A–E and G were taken at × 20 magnification and all others at × 40 magnification.
Mentions: Hypoxia-inducible factor-1α protein was not expressed in normal breast tissue, but was expressed in the nuclei of ductal epithelial cells in 65–75% of hyperplastic breast/in situ cancers (Figures 2A and 3A) and in over 90% of invasive cancers (Figures 2B and 3A). There was a moderate correlation between HIF-1α expression and MVD (Spearman's rho correlation coefficient=0.502, P=0.001) and proliferating ECs (Spearman's rho correlation coefficient=0.301, P=0.001). The correlation coefficients for inter- and intraobserver error scores for HIF-1α assessment were 0.88 and 0.91, respectively, showing a high level of agreement.

Bottom Line: In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005).Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05).These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.

View Article: PubMed Central - PubMed

Affiliation: Microcirculation Research Group, Academic Unit of Surgical Oncology, University of Sheffield Medical School, Sheffield, South Yorkshire, UK.

ABSTRACT

Background: The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown.

Methods: Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens.

Results: Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P<0.005), and between in situ and invasive carcinomas (P<0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005). Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05). Moreover, HIF-1alpha was expressed by 60-75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (P<0.005) and invasive tumour cells (P<0.01).

Conclusions: These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.

Show MeSH
Related in: MedlinePlus