Cargando…

Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

INTRODUCTION: Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance...

Descripción completa

Detalles Bibliográficos
Autores principales: Kuijper, Arno, van der Groep, Petra, van der Wall, Elsken, van Diest, Paul J
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1242154/
https://www.ncbi.nlm.nih.gov/pubmed/16168127
http://dx.doi.org/10.1186/bcr1296
_version_ 1782125606666764288
author Kuijper, Arno
van der Groep, Petra
van der Wall, Elsken
van Diest, Paul J
author_facet Kuijper, Arno
van der Groep, Petra
van der Wall, Elsken
van Diest, Paul J
author_sort Kuijper, Arno
collection PubMed
description INTRODUCTION: Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance of HIF-1α and its downstream targets in phyllodes tumors and fibroadenomas of the breast. METHODS: The expression of HIF-1α, CAIX, VEGF and p53 was investigated by immunohistochemistry in a group of 37 primary phyllodes tumors and 30 fibroadenomas with known clinical follow-up. The tumor microvasculature was visualized by immunohistochemistry for CD31. Proliferation was assessed by Ki67 immunostaining and mitotic counts. Being biphasic tumors, immunoquantification was performed in the stroma and epithelium. RESULTS: Only two fibroadenomas displayed low-level stromal HIF-1α reactivity in the absence of CAIX expression. Stromal HIF-1α expression was positively correlated with phyllodes tumor grade (P = 0.001), with proliferation as measured by Ki67 expression (P < 0.001) and number of mitoses (P < 0.001), with p53 accumulation (P = 0.003), and with global (P = 0.015) and hot-spot (P = 0.031) microvessel counts, but not with CAIX expression. Interestingly, concerted CAIX and HIF-1α expression was frequently found in morphologically normal epithelium of phyllodes tumors. The distance from the epithelium to the nearest microvessels was higher in phyllodes tumors as compared with in fibroadenomas. Microvessel counts as such did not differ between fibroadenomas and phyllodes tumors, however. High expression of VEGF was regularly found in both tumors, with only a positive relation between stromal VEGF and grade in phyllodes tumors (P = 0.016). Stromal HIF-1α overexpression in phyllodes tumors was predictive of disease-free survival (P = 0.032). CONCLUSION: These results indicate that HIF-1α expression is associated with diminished disease-free survival and may play an important role in stromal progression of breast phyllodes tumors. In view of the absence of stromal CAIX expression in phyllodes tumors, stromal upregulation of HIF-1α most probably arises from hypoxia-independent pathways, with p53 inactivation as one possible cause. In contrast, coexpression of HIF-1α and CAIX in the epithelium in phyllodes tumors points to epithelial hypoxia, most probably caused by relatively distant blood vessels. On the other hand, HIF-1α and CAIX seem to be of minor relevance in breast fibroadenomas.
format Text
id pubmed-1242154
institution National Center for Biotechnology Information
language English
publishDate 2005
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-12421542005-10-06 Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast Kuijper, Arno van der Groep, Petra van der Wall, Elsken van Diest, Paul J Breast Cancer Res Research Article INTRODUCTION: Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance of HIF-1α and its downstream targets in phyllodes tumors and fibroadenomas of the breast. METHODS: The expression of HIF-1α, CAIX, VEGF and p53 was investigated by immunohistochemistry in a group of 37 primary phyllodes tumors and 30 fibroadenomas with known clinical follow-up. The tumor microvasculature was visualized by immunohistochemistry for CD31. Proliferation was assessed by Ki67 immunostaining and mitotic counts. Being biphasic tumors, immunoquantification was performed in the stroma and epithelium. RESULTS: Only two fibroadenomas displayed low-level stromal HIF-1α reactivity in the absence of CAIX expression. Stromal HIF-1α expression was positively correlated with phyllodes tumor grade (P = 0.001), with proliferation as measured by Ki67 expression (P < 0.001) and number of mitoses (P < 0.001), with p53 accumulation (P = 0.003), and with global (P = 0.015) and hot-spot (P = 0.031) microvessel counts, but not with CAIX expression. Interestingly, concerted CAIX and HIF-1α expression was frequently found in morphologically normal epithelium of phyllodes tumors. The distance from the epithelium to the nearest microvessels was higher in phyllodes tumors as compared with in fibroadenomas. Microvessel counts as such did not differ between fibroadenomas and phyllodes tumors, however. High expression of VEGF was regularly found in both tumors, with only a positive relation between stromal VEGF and grade in phyllodes tumors (P = 0.016). Stromal HIF-1α overexpression in phyllodes tumors was predictive of disease-free survival (P = 0.032). CONCLUSION: These results indicate that HIF-1α expression is associated with diminished disease-free survival and may play an important role in stromal progression of breast phyllodes tumors. In view of the absence of stromal CAIX expression in phyllodes tumors, stromal upregulation of HIF-1α most probably arises from hypoxia-independent pathways, with p53 inactivation as one possible cause. In contrast, coexpression of HIF-1α and CAIX in the epithelium in phyllodes tumors points to epithelial hypoxia, most probably caused by relatively distant blood vessels. On the other hand, HIF-1α and CAIX seem to be of minor relevance in breast fibroadenomas. BioMed Central 2005 2005-08-05 /pmc/articles/PMC1242154/ /pubmed/16168127 http://dx.doi.org/10.1186/bcr1296 Text en Copyright © 2005 Kuijper et al, licensee BioMed Central Ltd.
spellingShingle Research Article
Kuijper, Arno
van der Groep, Petra
van der Wall, Elsken
van Diest, Paul J
Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast
title Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast
title_full Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast
title_fullStr Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast
title_full_unstemmed Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast
title_short Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast
title_sort expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1242154/
https://www.ncbi.nlm.nih.gov/pubmed/16168127
http://dx.doi.org/10.1186/bcr1296
work_keys_str_mv AT kuijperarno expressionofhypoxiainduciblefactor1alphaanditsdownstreamtargetsinfibroepithelialtumorsofthebreast
AT vandergroeppetra expressionofhypoxiainduciblefactor1alphaanditsdownstreamtargetsinfibroepithelialtumorsofthebreast
AT vanderwallelsken expressionofhypoxiainduciblefactor1alphaanditsdownstreamtargetsinfibroepithelialtumorsofthebreast
AT vandiestpaulj expressionofhypoxiainduciblefactor1alphaanditsdownstreamtargetsinfibroepithelialtumorsofthebreast