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Heparanase Accelera...
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Hermano, EstherHadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel
(author)
Heparanase Accelerates Obesity-Associated Breast Cancer Progression
- Article/chapterEnglish2019
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LIBRIS-ID:oai:DiVA.org:uu-397635
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-397635URI
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https://doi.org/10.1158/0008-5472.CAN-18-4058DOI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages-key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients. Significance: This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.
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Goldberg, RachelHadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel
(author)
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Rubinstein, Ariel M.Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel
(author)
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Sonnenblick, AmirTel Aviv Univ, Tel Aviv Sourasky Med Ctr, Oncol Div, Tel Aviv, Israel; Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel
(author)
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Maly, BellaHadassah Hebrew Univ, Med Ctr, Dept Pathol, Jerusalem, Israel
(author)
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Nahmias, DanielaHadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel
(author)
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Li, Jin-PingUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi(Swepub:uu)jinpili
(author)
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Bakker, Marinka A. H.Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Dept Nephrol, Nephrol Res Lab,Med Ctr, Nijmegen, Netherlands
(author)
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van der Vlag, JohanRadboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Dept Nephrol, Nephrol Res Lab,Med Ctr, Nijmegen, Netherlands
(author)
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Vlodavsky, IsraelTechnion, Rappaport Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel
(author)
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Peretz, TamarHadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel; Hebrew Univ Jerusalem, Med Sch, Jerusalem, Israel
(author)
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Elkin, MichaelHadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, Israel; Hebrew Univ Jerusalem, Med Sch, Jerusalem, Israel
(author)
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Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Jerusalem, IsraelTel Aviv Univ, Tel Aviv Sourasky Med Ctr, Oncol Div, Tel Aviv, Israel; Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel
(creator_code:org_t)
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In:Cancer Research79:20, s. 5342-53540008-54721538-7445
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Hermano, Esther
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Goldberg, Rachel
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Rubinstein, Arie ...
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Sonnenblick, Ami ...
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Maly, Bella
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Nahmias, Daniela
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Li, Jin-Ping
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Bakker, Marinka ...
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van der Vlag, Jo ...
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Vlodavsky, Israe ...
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Peretz, Tamar
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Elkin, Michael
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- MEDICAL AND HEALTH SCIENCES
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Cancer Research
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Uppsala University