No Amplifications of Hypoxia-Inducible Factor-1α Gene in Invasive Breast Cancer: A Tissue Microarray Study

Objective: Hypoxia Inducible Factor‐1 (HIF‐1) is an important transcription factor that stimulates tumour growth and metastases via several pathways, including angiogenesis and altered metabolism. Activation of HIF‐1 depends on the levels of its α‐subunit, which increase during hypoxia. Recent studies showed that the HIF‐1α gene was amplified in prostate cancer, leading to overexpression of HIF‐1α at normoxia. The aim of this study was to evaluate the presence of HIF‐1α gene amplifications in invasive breast cancer as an explanation for HIF‐1α protein overexpression. Methods: Protein and gene expression of HIF‐1α were analyzed on a tissue microarray of 94 breast cancers by immunohistochemistry and fluorescent in situ hybridization (FISH), respectively. Results: Overexpression of HIF‐1α protein was found in 58/94 (62%) of patients. No amplifications of the HIF‐1α gene were detected. Conclusion: Increased protein levels of HIF‐1α are not associated with amplification of the HIF‐1α gene in human breast cancer. Therefore, other mechanisms than gene amplification must be responsible for HIF‐α overexpression at normoxia.

[1]  Tapio Visakorpi,et al.  Amplification of hypoxia-inducible factor 1α gene in prostate cancer , 2001 .

[2]  I. Ellis,et al.  Pathology and breast screening , 1990, Histopathology.

[3]  G. Semenza,et al.  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 , 1992, Molecular and cellular biology.

[4]  Adrian L. Harris,et al.  Hypoxia — a key regulatory factor in tumour growth , 2002, Nature Reviews Cancer.

[5]  D A Hilton,et al.  Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. , 1999, Cancer research.

[6]  T. Visakorpi,et al.  Amplification of hypoxia-inducible factor 1alpha gene in prostate cancer. , 2001, Cancer genetics and cytogenetics.

[7]  G. Semenza,et al.  Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Schindl,et al.  Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  R. Bruick.  Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  P. V. van Diest,et al.  Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma , 2003, Cancer.

[11]  A. Harris,et al.  Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer , 2005, Journal of Clinical Pathology.

[12]  G. Semenza,et al.  Levels of Hypoxia-Inducible Factor-1α During Breast Carcinogenesis , 2001 .

[13]  G. Semenza,et al.  Dimerization, DNA Binding, and Transactivation Properties of Hypoxia-inducible Factor 1* , 1996, The Journal of Biological Chemistry.

[14]  L. Salomon,et al.  Human hormone-refractory prostate cancers can harbor mutations in the O(2)-dependent degradation domain of hypoxia inducible factor-1alpha (HIF-1alpha). , 2002, Journal of cancer research and clinical oncology.

[15]  G. Semenza.  HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[16]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[17]  T. Visakorpi,et al.  Improved technique for analysis of formalin-fixed, paraffin-embedded tumors by fluorescence in situ hybridization. , 1994, Cytometry.

[18]  L. Salomon,et al.  Human hormone-refractory prostate cancers can harbor mutations in the O2-dependent degradation domain of hypoxia inducible factor-1α (HIF-1α) , 2002, Journal of Cancer Research and Clinical Oncology.

[19]  G. Semenza,et al.  Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. , 2001, Journal of the National Cancer Institute.

[20]  Klaus Pantel,et al.  Molecular signature associated with bone marrow micrometastasis in human breast cancer. , 2003, Cancer research.

[21]  G. Semenza,et al.  Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. , 1999, Annual review of cell and developmental biology.

[22]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[23]  D. Livingston,et al.  Activation of Hypoxia-inducible Transcription Factor Depends Primarily upon Redox-sensitive Stabilization of Its α Subunit* , 1996, The Journal of Biological Chemistry.

[24]  G. Semenza,et al.  Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[25]  H Buerger,et al.  Demystified … Tissue microarray technology , 2003, Molecular pathology : MP.