Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma

Reinhard Bos, Petra Van der Groep, Astrid E. Greijer, Avi Shvarts, Sybren Meijer, Herbert M. Pinedo, Gregg L Semenza, Paul J. Van Diest, Elsken Van der Wall

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF-1α, the O2-regulated subunit of HIF-1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF-1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated. METHODS. Expression levels of HIF-1α, HER-2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early-stage breast carcinoma by immunohistochemistry. HER-2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease-free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two-sided univariate and multivariate tests, with P values <0.05 considered significant. RESULTS. High levels of HIF-1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease-free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER-2/neu immunoreactivity (P <0.001) and gene amplification (P <0.001), vascular endothelial growth factor expression (P = 0.016), and Ki-67 expression (P <0.001) were correlated strongly with HIF-1α positivity, although none of those factors had an independent effect on survival. CONCLUSIONS. Increased levels of HIF-la were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF-1α as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma.

Original languageEnglish (US)
Pages (from-to)1573-1581
Number of pages9
JournalCancer
Volume97
Issue number6
DOIs
StatePublished - Mar 15 2003

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Hypoxia-Inducible Factor 1
Lymph Nodes
Breast Neoplasms
erbB-2 Genes
Survival
Gene Amplification
Disease-Free Survival
Neoplasms
ErbB-2 Receptor
Cell Hypoxia
Mitotic Index
Progesterone Receptors
Hematoxylin
Fluorescence In Situ Hybridization
Estrogen Receptors
Energy Metabolism
Vascular Endothelial Growth Factor A
Carcinogenesis
Breast
Transcription Factors

Keywords

  • Breast carcinoma
  • Estrogen receptor
  • HER-2/neu
  • Hypoxia-inducible factor 1α
  • Mitotic activity index
  • Progesterone receptor
  • Prognosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bos, R., Van der Groep, P., Greijer, A. E., Shvarts, A., Meijer, S., Pinedo, H. M., ... Van der Wall, E. (2003). Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer, 97(6), 1573-1581. https://doi.org/10.1002/cncr.11246

Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. / Bos, Reinhard; Van der Groep, Petra; Greijer, Astrid E.; Shvarts, Avi; Meijer, Sybren; Pinedo, Herbert M.; Semenza, Gregg L; Van Diest, Paul J.; Van der Wall, Elsken.

In: Cancer, Vol. 97, No. 6, 15.03.2003, p. 1573-1581.

Research output: Contribution to journalArticle

Bos, R, Van der Groep, P, Greijer, AE, Shvarts, A, Meijer, S, Pinedo, HM, Semenza, GL, Van Diest, PJ & Van der Wall, E 2003, 'Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma', Cancer, vol. 97, no. 6, pp. 1573-1581. https://doi.org/10.1002/cncr.11246
Bos, Reinhard ; Van der Groep, Petra ; Greijer, Astrid E. ; Shvarts, Avi ; Meijer, Sybren ; Pinedo, Herbert M. ; Semenza, Gregg L ; Van Diest, Paul J. ; Van der Wall, Elsken. / Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. In: Cancer. 2003 ; Vol. 97, No. 6. pp. 1573-1581.
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abstract = "BACKGROUND. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF-1α, the O2-regulated subunit of HIF-1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF-1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated. METHODS. Expression levels of HIF-1α, HER-2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early-stage breast carcinoma by immunohistochemistry. HER-2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease-free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two-sided univariate and multivariate tests, with P values <0.05 considered significant. RESULTS. High levels of HIF-1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease-free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER-2/neu immunoreactivity (P <0.001) and gene amplification (P <0.001), vascular endothelial growth factor expression (P = 0.016), and Ki-67 expression (P <0.001) were correlated strongly with HIF-1α positivity, although none of those factors had an independent effect on survival. CONCLUSIONS. Increased levels of HIF-la were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF-1α as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma.",
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author = "Reinhard Bos and {Van der Groep}, Petra and Greijer, {Astrid E.} and Avi Shvarts and Sybren Meijer and Pinedo, {Herbert M.} and Semenza, {Gregg L} and {Van Diest}, {Paul J.} and {Van der Wall}, Elsken",
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T1 - Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma

AU - Bos, Reinhard

AU - Van der Groep, Petra

AU - Greijer, Astrid E.

AU - Shvarts, Avi

AU - Meijer, Sybren

AU - Pinedo, Herbert M.

AU - Semenza, Gregg L

AU - Van Diest, Paul J.

AU - Van der Wall, Elsken

PY - 2003/3/15

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N2 - BACKGROUND. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF-1α, the O2-regulated subunit of HIF-1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF-1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated. METHODS. Expression levels of HIF-1α, HER-2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early-stage breast carcinoma by immunohistochemistry. HER-2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease-free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two-sided univariate and multivariate tests, with P values <0.05 considered significant. RESULTS. High levels of HIF-1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease-free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER-2/neu immunoreactivity (P <0.001) and gene amplification (P <0.001), vascular endothelial growth factor expression (P = 0.016), and Ki-67 expression (P <0.001) were correlated strongly with HIF-1α positivity, although none of those factors had an independent effect on survival. CONCLUSIONS. Increased levels of HIF-la were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF-1α as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma.

AB - BACKGROUND. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF-1α, the O2-regulated subunit of HIF-1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF-1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated. METHODS. Expression levels of HIF-1α, HER-2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early-stage breast carcinoma by immunohistochemistry. HER-2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease-free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two-sided univariate and multivariate tests, with P values <0.05 considered significant. RESULTS. High levels of HIF-1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease-free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER-2/neu immunoreactivity (P <0.001) and gene amplification (P <0.001), vascular endothelial growth factor expression (P = 0.016), and Ki-67 expression (P <0.001) were correlated strongly with HIF-1α positivity, although none of those factors had an independent effect on survival. CONCLUSIONS. Increased levels of HIF-la were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF-1α as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma.

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KW - Estrogen receptor

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KW - Hypoxia-inducible factor 1α

KW - Mitotic activity index

KW - Progesterone receptor

KW - Prognosis

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