title: Heparanase augments insulin receptor signaling in breast carcinoma.
abstract: Recently, growing interest in the potential link between metabolic disorders (i.e., diabetes, obesity, metabolic syndrome) and breast cancer has mounted, including studies which indicate that diabetic/hyperinsulinemic women have a significantly higher risk of bearing breast tumors that are more aggressive and associated with higher death rates. Insulin signaling is regarded as a major contributor to this phenomenon; much less is known about the role of heparan sulfate-degrading enzyme heparanase in the link between metabolic disorders and cancer.In the present study we analyzed clinical samples of breast carcinoma derived from diabetic/non-diabetic patients, and investigated effects of heparanase on insulin signaling in breast carcinoma cell lines, as well as insulin-driven growth of breast tumor cells.We demonstrate that heparanase activity leads to enhanced insulin signaling and activation of downstream tumor-promoting pathways in breast carcinoma cells. In agreement, heparanase enhances insulin-induced proliferation of breast tumor cells in vitro. Moreover, analyzing clinical data from diabetic breast carcinoma patients, we found that concurrent presence of both diabetic state and heparanase in tumor tissue (as opposed to either condition alone) was associated with more aggressive phenotype of breast tumors in the patient cohort analyzed in our study (two-sided Fisher's exact test; p=0.04). Our findings highlight the emerging role of heparanase in powering effect of hyperinsulinemic state on breast tumorigenesis and imply that heparanase targeting, which is now under intensive development/clinical testing, could be particularly efficient in a growing fraction of breast carcinoma patients suffering from metabolic disorders.
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Goldberg
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Sonnenblick
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Hermano
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Hamburger
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Amichay
authors.initials: A
authors.lastname: Meirovitz
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000503:physiopathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000099175:Heparanase
chemical_list: D014408:Biomarkers, Tumor; D005966:Glucuronidase; D011972:Receptor, Insulin; D000099175:Heparanase
keywords: breast carcinoma; diabetes; heparanase; insulin receptor