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Breast Cancer Research and Treatment

Published in:

01-08-2008 | Preclinical Study

Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer

Authors: Yutaka Yamamoto, Mutsuko Ibusuki, Yasuhiro Okumura, Teru Kawasoe, Kazuharu Kai, Kenichi Iyama, Hirotaka Iwase

Published in: Breast Cancer Research and Treatment | Issue 3/2008

Abstract

Purpose

The aim of this study is to clarify characteristics of invasive breast cancer with expression of Hypoxia-induced factor 1α (HIF-1α) which is induced by hypoxia and signal transduction of growth factors.

Experimental Design

We examined, by immunohistochemical analysis, the expression of HIF-1α in normal breast tissue, benign disorders and breast cancer. In invasive breast cancer, we investigated the correlation between expression of HIF-1α and clinicopathological and biological factors. We also studied the prognostic value of HIF-1α in breast cancer.

Results

HIF-1α was mainly detected in tumor cell nuclei. In the 171 cases of invasive breast cancer examined, nuclear HIF-1α expression was detected in 63 (36.8%) cases. Immunoreactive nuclear HIF-1α was correlated with tumor size (p = 0.0013), lymph node metastasis (p = 0.0005), tumor stage (p = 0.0031) and histological grade (p = 0.0074). Elevated HIF-1α levels was also associated with hormone receptor negativity (p = 0.0025), HER2 overexpression (p = 0.0053), high Ki67 labeling index (p = 0.0002), increased levels of VEGF (p < 0.0001), COX-2 overexpression (p = 0.0029) and increased nuclear p53 (p = 0.0048). In terms of the possible use of HIF-1α as a prognostic indicator, patients who had increased HIF-1α levels in their tumor showed shorter disease-free survival (DFS) (p < 0.0001) and overall survival (OS) (p = 0.0002) than those lacking HIF-1α in univariate analysis. In multivariate analysis of DFS and OS, HIF-1α was identified an independent prognostic factor.

Conclusions

These findings suggest that HIF-1α was closely linked to an aggressive phenotype in breast cancer. It may be useful to study the expression of HIF-1α using immunohistochemical analysis for better understanding of the tumor characteristics of breast cancer.

Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49(23):6449–6465PubMed

Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12(12):5447–5454PubMed

Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93(4):266–276PubMedCrossRef

Wang GL et al (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92(12): 5510–5514PubMedCrossRef

Huang LE et al (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 271(50):32253–32259PubMedCrossRef

Fukuda R et al (2002) Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 277(41):38205–38211PubMedCrossRef

Zhong H et al (2000) Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60(6):1541–1545PubMed

Cockman ME et al (2000) Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275(33):25733–25741PubMedCrossRef

Maxwell PH et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275PubMedCrossRef

10.

Ohh M et al (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2(7):423–427PubMedCrossRef

11.

Talks KL et al (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157(2):411–421PubMed

12.

Zhong H et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59(22):5830–5835PubMed

13.

Aebersold DM et al (2001) Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61(7):2911–2916PubMed

14.

Bachtiary B et al (2003) Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin Cancer Res 9(6):2234–2240PubMed

15.

Unruh A et al (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22(21):3213–3220PubMedCrossRef

16.

Bos R et al (2003) Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97(6):1573–1581PubMedCrossRef

17.

Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19(5):403–410PubMedCrossRef

18.

Bos R et al (2001) Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 93(4):309–314PubMedCrossRef

19.

Hudson CC et al (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22(20):7004–7014PubMedCrossRef

20.

Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732PubMedCrossRef

21.

Vleugel MM et al (2005) Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer. J Clin Pathol 58(2):172–177PubMedCrossRef

22.

Giatromanolaki A et al (2004) c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent. Clin Cancer Res 10(23):7972–7977PubMedCrossRef

23.

Gruber G et al (2004) Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter? Breast Cancer Res 6(3):R191–198PubMedCrossRef

24.

Kurebayashi J et al (2001) A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts. Jpn J Cancer Res 92(12):1342–1351PubMed

25.

Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 3(4):237–252PubMed

26.

Toi M et al (1996) Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer 77(6):1101–1106PubMedCrossRef

27.

Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676PubMedCrossRef

28.

Forsythe JA et al (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9):4604–4613PubMed

29.

Levy AP et al (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270(22):13333–13340PubMedCrossRef

30.

Ristimaki A et al (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62(3):632–635PubMed

31.

Zhong H, Willard M, Simons J (2004) NS398 reduces hypoxia-inducible factor (HIF)-1alpha and HIF-1 activity: multiple-level effects involving cyclooxygenase-2 dependent and independent mechanisms. Int J Cancer 112(4):585–595PubMedCrossRef

32.

Giaccia AJ, Kastan MB (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 12(19):2973–2983PubMedCrossRef

33.

Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88(3):323–331PubMedCrossRef

34.

Bos R et al (2004) Expression of hypoxia-inducible factor-1alpha and cell cycle proteins in invasive breast cancer are estrogen receptor related. Breast Cancer Res 6(4):R450–459PubMedCrossRef

35.

Carmeliet P et al (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394(6692):485–490PubMedCrossRef

36.

An WG et al (1998) Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392(6674):405–408PubMedCrossRef

37.

Ravi R et al (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14(1):34–44PubMed

38.

Bergh J et al (1995) Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat Med 1(10):1029–1034PubMedCrossRef

39.

Sjogren S et al (1996) The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 88(3–4):173–182PubMedCrossRef

40.

Theodoropoulos VE et al (2004) Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 46(2):200–208PubMedCrossRef

41.

Swinson DE et al (2004) Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer 111(1):43–50PubMedCrossRef

42.

Duff SE et al (2003) CD105 is important for angiogenesis: evidence and potential applications. Faseb J 17(9):984–992PubMedCrossRef

43.

Schindl M et al (2002) Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8(6):1831–1837PubMed

44.

Dales JP et al (2005) Overexpression of hypoxia-inducible factor HIF-1alpha predicts early relapse in breast cancer: retrospective study in a series of 745 patients. Int J Cancer 116(5):734–739PubMedCrossRef

45.

Birner P et al (2001) Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer 92(1):165–171PubMedCrossRef

46.

Birner P et al (2000) Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 60(17):4693–4696PubMed

Title: Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer
Authors: Yutaka Yamamoto
Mutsuko Ibusuki
Yasuhiro Okumura
Teru Kawasoe
Kazuharu Kai
Kenichi Iyama
Hirotaka Iwase
Publication date: 01-08-2008
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2008
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-007-9742-1

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Abstract

Purpose

Experimental Design

Results

Conclusions

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