Regulation of heparanase gene expression by estrogen in breast cancer.
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.
Elkin
Michael
M
Cell Biology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892, USA
Cohen
Irit
I
Zcharia
Eyal
E
Orgel
Adam
A
Guatta-Rangini
Zehava
Z
Peretz
Tamar
T
Vlodavsky
Israel
I
Kleinman
Hynda K
HK
D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D004967:Estrogens / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D005966:Glucuronidase / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D020218:Response Elements; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation; D000099175:Heparanase
D004967:Estrogens; D005966:Glucuronidase; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D000099175:Heparanase