| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
1 Cell Biology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland;
2 Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and
3 Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Haifa, Israel
Numerous epidemiological studies clearly suggest that estrogen is one of the main driving forces in breast tumorigenesis, but precise mechanisms of cancer promotion by estrogen remain poorly understood. Classically, tumorigenic effects of estrogen have been attributed to its ability to directly promote the proliferation of breast cancer cells. In addition to abnormal proliferation, interactions between tumor cells and surrounding stromal components (e.g., enzymatic remodeling and degradation of extracellular matrix) are critical for cancer progression, angiogenesis, and metastasis. We now report that in breast carcinomas, estrogen may promote these pathological tumor-stromal interactions through up-regulation of heparanase gene expression. Heparanase is an endoglycosidase degrading heparan sulfate, of the basement membrane and extracellular matrix. This cleavage affects tumor-stromal interaction, neovascularization, local invasion, and metastatic spread. However, little is known about transcriptional regulation of the heparanase gene. We identified four putative estrogen response elements in the heparanase promoter region and found that transcription of a luciferase reporter gene driven by the heparanase promoter was significantly increased in estrogen-receptor positive MCF-7 human breast carcinoma cells after estrogen treatment. Estrogen-induced heparanase mRNA transcription in estrogen receptor-positive, but not in estrogen receptor-negative, breast cancer cells, confirmed the promoter study data. The estrogen effects on heparanase mRNA expression levels were abolished in the presence of the pure antiestrogen ICI 182,780, indicating that the classic estrogen receptor pathway is involved in transcriptional activation of heparanase. In vivo, exposure to estrogen augmented levels of heparanase protein in MCF-7 cells embedded in Matrigel plugs and correlated with increased plug vascularization. Collectively, our data suggest a new molecular pathway through which estrogen, independent of its proliferative effect, may induce heparanase overexpression and, thus, promote tumor-stromal interactions, critical for breast carcinoma development and progression.
This article has been cited by other articles:
|
|
 |
|
  I. Cohen, B. Maly, I. Simon, A. Meirovitz, E. Pikarsky, E. Zcharia, T. Peretz, I. Vlodavsky, and M. Elkin Tamoxifen Induces Heparanase Expression in Estrogen Receptor Positive Breast Cancer Clin. Cancer Res., July 15, 2007; 13(14): 4069 - 4077. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Xu, J. Ding, G. Rao, J. Shen, R. A. Prinz, N. Rana, and W.P. Dmowski Estradiol induces heparanase-1 expression and heparan sulphate proteoglycan degradation in human endometrium Hum. Reprod., April 1, 2007; 22(4): 927 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gotte and G. W. Yip Heparanase, Hyaluronan, and CD44 in Cancers: A Breast Carcinoma Perspective Cancer Res., November 1, 2006; 66(21): 10233 - 10237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Edovitsky, I. Lerner, E. Zcharia, T. Peretz, I. Vlodavsky, and M. Elkin Role of endothelial heparanase in delayed-type hypersensitivity Blood, May 1, 2006; 107(9): 3609 - 3616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-M. Cleton-Jansen, H. M. van Beerendonk, H. J. Baelde, J. V.G.M. Bovee, M. Karperien, and P. C.W. Hogendoorn Estrogen Signaling Is Active in Cartilaginous Tumors: Implications for Antiestrogen Therapy as Treatment Option of Metastasized or Irresectable Chondrosarcoma Clin. Cancer Res., November 15, 2005; 11(22): 8028 - 8035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. de Mestre, S. Rao, J. R. Hornby, T. Soe-Htwe, L. M. Khachigian, and M. D. Hulett Early Growth Response Gene 1 (EGR1) Regulates Heparanase Gene Transcription in Tumor Cells J. Biol. Chem., October 21, 2005; 280(42): 35136 - 35147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Maxhimer, M. Somenek, G. Rao, C. E. Pesce, D. Baldwin Jr., P. Gattuso, M. M. Schwartz, E. J. Lewis, R. A. Prinz, and X. Xu Heparanase-1 Gene Expression and Regulation by High Glucose in Renal Epithelial Cells: A Potential Role in the Pathogenesis of Proteinuria in Diabetic Patients Diabetes, July 1, 2005; 54(7): 2172 - 2178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Beckhove, B. M. Helmke, Y. Ziouta, M. Bucur, W. Dorner, C. Mogler, G. Dyckhoff, and C. Herold-Mende Heparanase Expression at the Invasion Front of Human Head and Neck Cancers and Correlation with Poor Prognosis Clin. Cancer Res., April 15, 2005; 11(8): 2899 - 2906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Zcharia, D. Philp, E. Edovitsky, H. Aingorn, S. Metzger, H. K. Kleinman, I. Vlodavsky, and M. Elkin Heparanase Regulates Murine Hair Growth Am. J. Pathol., April 1, 2005; 166(4): 999 - 1008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gingis-Velitski, A. Zetser, V. Kaplan, O. Ben-Zaken, E. Cohen, F. Levy-Adam, Y. Bashenko, M. Y. Flugelman, I. Vlodavsky, and N. Ilan Heparanase Uptake Is Mediated by Cell Membrane Heparan Sulfate Proteoglycans J. Biol. Chem., October 15, 2004; 279(42): 44084 - 44092. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
