{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:54:20Z","timestamp":1785412460108,"version":"3.56.0"},"reference-count":99,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2292\/21"],"award-info":[{"award-number":["2292\/21"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2292\/21"],"award-info":[{"award-number":["2292\/21"]}],"id":[{"id":"https:\/\/ror.org\/04sazxf24","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003975","name":"Israel Cancer Association","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003975","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03yxd7304","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001698","name":"Israel Cancer Research Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001698","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity has been consistently associated with several types of malignant tumors, including hormone-responsive breast carcinoma (BC) in postmenopausal patients. BC is the most diagnosed malignancy and the leading cause of cancer-related morbidity and mortality among women worldwide. The predominant association between obesity and hormone-responsive BC subtypes is often explained by the increased local production of estrogens due to upregulation of aromatase, the rate-limiting enzyme in estrogen biosynthesis, in the chronically inflamed \u201cobese\u201d adipose tissue. However, the underlying molecular mechanisms are not fully defined. One potential mediator of inflammatory responses in the setting of obesity is bacterial endotoxin. Indeed, subclinical concentrations of endotoxin are chronically present in the circulation of obese patients and experimental animals (the phenomenon termed \u2018metabolic endotoxemia\u2019 [ME]). Here, we investigated whether ME conditions are mechanistically involved in augmented estrogen reactivity that sustains the obesity-BC link, focusing primarily on ME effects on key cellular components of the BC microenvironment (i.e., fibroblasts, macrophages). Our findings identify ME as a microenvironmental driver that directly induces aromatase expression in adipose fibroblasts, and simultaneously triggers upregulation of estrogen receptor levels in breast tumor cells via a macrophage-mediated mechanism. This dual action of ME in fueling obesity-accelerated hormone-dependent breast tumorigenesis may suggest new avenues for both therapeutic intervention and prevention of BC-promoting consequences of excess adiposity in an increasingly obese population.<\/jats:p>","DOI":"10.3390\/ijms27104338","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:26:37Z","timestamp":1778689597000},"page":"4338","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Endotoxemia Amplifies Estrogen Signaling Through Stromal Crosstalk in Obesity-Associated Breast Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Emmy","family":"Drai","sequence":"first","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Nahmias Blank","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Hermano","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Yifrach","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5603-983X","authenticated-orcid":false,"given":"Ofer","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofra","family":"Maimon","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aron","family":"Popovtzer","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Peretz","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7479-2926","authenticated-orcid":false,"given":"Amichay","family":"Meirovitz","sequence":"additional","affiliation":[{"name":"Legacy Heritage Oncology Center and Dr. Larry Norton Institute, Soroka University Medical Center, Be\u2019er Sheva 84101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Elkin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.2337\/db06-1491","article-title":"Metabolic endotoxemia initiates obesity and insulin resistance","volume":"56","author":"Cani","year":"2007","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41467-017-00163-w","article-title":"Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity","volume":"8","author":"Cao","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1093\/ajcn\/87.5.1219","article-title":"Energy intake is associated with endotoxemia in apparently healthy men","volume":"87","author":"Amar","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.biochi.2015.06.020","article-title":"Metabolic endotoxemia with obesity: Is it real and is it relevant?","volume":"124","author":"Boutagy","year":"2016","journal-title":"Biochimie"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.2337\/dc13-0451","article-title":"Plasma lipopolysaccharide is closely associated with glycemic control and abdominal obesity: Evidence from bariatric surgery","volume":"36","author":"Troseid","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fuke, N., Nagata, N., Suganuma, H., and Ota, T. (2019). Regulation of Gut Microbiota and Metabolic Endotoxemia with Dietary Factors. Nutrients, 11.","DOI":"10.3390\/nu11102277"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s40168-024-01901-1","article-title":"Visceral adiposity in postmenopausal women is associated with a pro-inflammatory gut microbiome and immunogenic metabolic endotoxemia","volume":"12","author":"Gaber","year":"2024","journal-title":"Microbiome"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nahmias Blank, D., Maimon, O., Hermano, E., Drai, E., Chen, O., Popovtzer, A., Peretz, T., Meirovitz, A., and Elkin, M. (2025). Unraveling the Role of Metabolic Endotoxemia in Accelerating Breast Tumor Progression. Biomedicines, 13.","DOI":"10.3390\/biomedicines13081868"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1126\/science.aar3318","article-title":"Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection","volume":"359","author":"Thaiss","year":"2018","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3070","DOI":"10.4049\/jimmunol.176.5.3070","article-title":"Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier","volume":"176","author":"Neal","year":"2006","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.4049\/jimmunol.170.3.1399","article-title":"Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons","volume":"170","author":"Vreugdenhil","year":"2003","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1017\/S0954422417000269","article-title":"Role of microbiota-derived lipopolysaccharide in adipose tissue inflammation, adipocyte size and pyroptosis during obesity","volume":"31","author":"Hersoug","year":"2018","journal-title":"Nutr. Res. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E319","DOI":"10.1152\/ajpendo.00277.2018","article-title":"Metabolic endotoxemia promotes adipose dysfunction and inflammation in human obesity","volume":"316","author":"Lhamyani","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R51","DOI":"10.1530\/JME-13-0079","article-title":"Metabolic endotoxemia: A molecular link between obesity and cardiovascular risk","volume":"51","author":"Neves","year":"2013","journal-title":"J. Mol. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Massier, L., Bluher, M., Kovacs, P., and Chakaroun, R.M. (2021). Impaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.616506"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1038\/s41366-022-01193-1","article-title":"Possible mediators of metabolic endotoxemia in women with obesity and women with obesity-diabetes in The Gambia","volume":"46","author":"Jobe","year":"2022","journal-title":"Int. J. Obes."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Manilla, V., Di Tommaso, N., Santopaolo, F., Gasbarrini, A., and Ponziani, F.R. (2023). Endotoxemia and Gastrointestinal Cancers: Insight into the Mechanisms Underlying a Dangerous Relationship. Microorganisms, 11.","DOI":"10.3390\/microorganisms11020267"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Eibl, G., and Rozengurt, E. (2021). Obesity and Pancreatic Cancer: Insight into Mechanisms. Cancers, 13.","DOI":"10.3390\/cancers13205067"},{"key":"ref_19","unstructured":"NCI (2026, April 29). Obesity and Cancer Fact Sheet\u2014NCI, Available online: https:\/\/www.cancer.gov\/about-cancer\/causes-prevention\/risk\/obesity\/obesity-fact-sheet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.soard.2023.01.025","article-title":"Excess body fatness and cancer risk: A summary of the epidemiologic evidence","volume":"19","author":"Patel","year":"2023","journal-title":"Surg. Obes. Relat. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1038\/s41591-026-04219-7","article-title":"Global and regional cancer burden attributable to modifiable risk factors to inform prevention","volume":"32","author":"Fink","year":"2026","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.ccr.2012.02.007","article-title":"Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4","volume":"21","author":"Dapito","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/pros.20710","article-title":"The toll-like receptor pathway: A novel mechanism of infection-induced carcinogenesis of prostate epithelial cells","volume":"68","author":"Kundu","year":"2008","journal-title":"Prostate"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27051","DOI":"10.1038\/srep27051","article-title":"LPS\/TLR4 Signaling Enhances TGF-beta Response Through Downregulating BAMBI During Prostatic Hyperplasia","volume":"6","author":"He","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.semcancer.2023.09.003","article-title":"Excess body weight and postmenopausal breast cancer: Emerging molecular mechanisms and perspectives","volume":"96","author":"Maimon","year":"2023","journal-title":"Semin. Cancer Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/j.cmet.2020.05.008","article-title":"The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development","volume":"31","author":"Qureshi","year":"2020","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8074","DOI":"10.1002\/cam4.3295","article-title":"EO771, is it a well-characterized cell line for mouse mammary cancer model? Limit and uncertainty","volume":"9","author":"Rossary","year":"2020","journal-title":"Cancer Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00774-018-0927-y","article-title":"Establishment and characterization of a C57BL\/6 mouse model of bone metastasis of breast cancer","volume":"37","author":"Hiraga","year":"2019","journal-title":"J. Bone Miner. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"514","DOI":"10.4161\/cbt.8.6.7689","article-title":"Oral administration of pyrrolidine dithiocarbamate (PDTC) inhibits VEGF expression, tumor angiogenesis, and growth of breast cancer in female mice","volume":"8","author":"Gu","year":"2009","journal-title":"Cancer Biol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1038\/s41388-025-03521-x","article-title":"Oncogenic effects of ECM remodeling in obesity and breast cancer","volume":"44","author":"Hawes","year":"2025","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13046-022-02592-y","article-title":"Cancer-educated mammary adipose tissue-derived stromal\/stem cells in obesity and breast cancer: Spatial regulation and function","volume":"42","author":"Ritter","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s10555-022-10031-9","article-title":"Breast cancer microenvironment and obesity: Challenges for therapy","volume":"41","author":"Kuziel","year":"2022","journal-title":"Cancer Metastasis Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4270","DOI":"10.1200\/JCO.2016.67.4283","article-title":"Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation","volume":"34","author":"Iyengar","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1158\/1940-6207.CAPR-11-0110","article-title":"Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer","volume":"4","author":"Morris","year":"2011","journal-title":"Cancer Prev. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1677\/erc.0.0060139","article-title":"The regulation of aromatase activity in breast fibroblasts: The role of interleukin-6 and prostaglandin E2","volume":"6","author":"Singh","year":"1999","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1002\/ijc.23943","article-title":"Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status\u2014A meta-analysis","volume":"124","author":"Suzuki","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3700","DOI":"10.1002\/cncr.29552","article-title":"Overall and central adiposity and breast cancer risk in the Sister Study","volume":"121","author":"White","year":"2015","journal-title":"Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1001\/jamaoncol.2015.1546","article-title":"Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk: A Secondary Analysis of the Women\u2019s Health Initiative Randomized Clinical Trials","volume":"1","author":"Neuhouser","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1056\/NEJMsr1606602","article-title":"Body Fatness and Cancer\u2014Viewpoint of the IARC Working Group","volume":"375","author":"Scoccianti","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"283","DOI":"10.4048\/jbc.2016.19.3.283","article-title":"Increased Incidence of Breast Cancer in Postmenopausal Women with High Body Mass Index at the Modena Screening Program","volume":"19","author":"Sebastiani","year":"2016","journal-title":"J. Breast Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1016\/S2213-8587(18)30150-5","article-title":"Worldwide burden of cancer attributable to diabetes and high body-mass index: A comparative risk assessment","volume":"6","author":"Zhou","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s11912-019-0787-1","article-title":"The Impact of Obesity on Breast Cancer Diagnosis and Treatment","volume":"21","author":"Lee","year":"2019","journal-title":"Curr. Oncol. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yang, T.O., Cairns, B.J., Pirie, K., Green, J., Beral, V., Floud, S., and Reeves, G.K. (2022). Body size in early life and the risk of postmenopausal breast cancer. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09233-9"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41574-025-01208-7","article-title":"Oestrogen changes at menopause: Insights into obesity-associated breast risk and outcomes","volume":"22","author":"Sho","year":"2025","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e35911","DOI":"10.1002\/cncr.35911","article-title":"Body mass index and breast cancer risk among postmenopausal women with and without cardiometabolic diseases: Findings from two prospective cohort studies in Europe","volume":"131","author":"Fontvieille","year":"2025","journal-title":"Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4465","DOI":"10.1158\/0008-5472.CAN-20-0789","article-title":"Targeting Obesity-Induced Macrophages during Preneoplastic Growth Promotes Mammary Epithelial Stem\/Progenitor Activity, DNA Damage, and Tumor Formation","volume":"80","author":"Chamberlin","year":"2020","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Nahmias Blank, D., Hermano, E., Sonnenblick, A., Maimon, O., Rubinstein, A.M., Drai, E., Maly, B., Vlodavsky, I., Popovtzer, A., and Peretz, T. (2022). Macrophages Upregulate Estrogen Receptor Expression in the Model of Obesity-Associated Breast Carcinoma. Cells, 11.","DOI":"10.3390\/cells11182844"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.tem.2011.10.003","article-title":"Aromatase, breast cancer and obesity: A complex interaction","volume":"23","author":"Bulun","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_49","first-page":"1350","article-title":"Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4","volume":"10","author":"Zhao","year":"1996","journal-title":"Mol. Endocrinol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/S0039-128X(02)00046-6","article-title":"Regulation of estrogen synthesis in postmenopausal women","volume":"67","author":"Purohit","year":"2002","journal-title":"Steroids"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"T51","DOI":"10.1530\/JME-13-0217","article-title":"Obesity and breast cancer: Role of inflammation and aromatase","volume":"51","author":"Simpson","year":"2013","journal-title":"J. Mol. Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.coph.2016.11.003","article-title":"Inflammation, dysregulated metabolism and aromatase in obesity and breast cancer","volume":"31","author":"Zahid","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.tcb.2022.02.008","article-title":"Extracellular matrix remodeling facilitates obesity-associated cancer progression","volume":"32","author":"Kim","year":"2022","journal-title":"Trends Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1210\/jc.2016-3606","article-title":"Menopause Is a Determinant of Breast Aromatase Expression and Its Associations with BMI, Inflammation, and Systemic Markers","volume":"102","author":"Brown","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1172\/JCI57132","article-title":"Inflammatory links between obesity and metabolic disease","volume":"121","author":"Lumeng","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1177\/0890334405276471","article-title":"Breast fat and fallacies: More than 100 years of anatomical fantasy","volume":"21","author":"Nickell","year":"2005","journal-title":"J. Hum. Lact."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0960-0760(03)00360-1","article-title":"Sources of estrogen and their importance","volume":"86","author":"Simpson","year":"2003","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.4049\/jimmunol.1200857","article-title":"Molecular mechanisms responsible for the selective and low-grade induction of proinflammatory mediators in murine macrophages by lipopolysaccharide","volume":"189","author":"Maitra","year":"2012","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0022-1759(94)90005-1","article-title":"Markers of mouse macrophage development detected by monoclonal antibodies","volume":"174","author":"Leenen","year":"1994","journal-title":"J. Immunol. Methods"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.4049\/jimmunol.180.4.2650","article-title":"Regulation of alternative macrophage activation by galectin-3","volume":"180","author":"MacKinnon","year":"2008","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1007\/s12282-021-01217-0","article-title":"Podoplanin expression in cancer-associated fibroblasts predicts unfavorable prognosis in node-negative breast cancer patients with hormone receptor-positive\/HER2\u2014Negative subtype","volume":"28","author":"Tanaka","year":"2021","journal-title":"Breast Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e16958","DOI":"10.7717\/peerj.16958","article-title":"The relationship between cancer associated fibroblasts biomarkers and prognosis of breast cancer: A systematic review and meta-analysis","volume":"12","author":"Cui","year":"2024","journal-title":"PeerJ"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6080","DOI":"10.1158\/0008-5472.CAN-13-0926","article-title":"Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis","volume":"73","author":"Arendt","year":"2013","journal-title":"Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5342","DOI":"10.1158\/0008-5472.CAN-18-4058","article-title":"Heparanase Accelerates Obesity-Associated Breast Cancer Progression","volume":"79","author":"Hermano","year":"2019","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1158\/1078-0432.CCR-15-1839","article-title":"PlGF\/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity","volume":"22","author":"Incio","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1158\/0008-5472.CAN-15-1260","article-title":"Infiltrating Macrophages Induce ERalpha Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen","volume":"76","author":"Ning","year":"2016","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"907","DOI":"10.5858\/134.6.907","article-title":"American Society of Clinical Oncology\/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer","volume":"134","author":"Hammond","year":"2010","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/s41574-021-00487-0","article-title":"Metabolic pathways in obesity-related breast cancer","volume":"17","author":"Brown","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s11912-018-0688-8","article-title":"The Impact of Obesity on Breast Cancer","volume":"20","author":"Argolo","year":"2018","journal-title":"Curr. Oncol. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1038\/oby.2006.191","article-title":"Relation of BMI and physical activity to sex hormones in postmenopausal women","volume":"14","author":"McTiernan","year":"2006","journal-title":"Obesity"},{"key":"ref_71","first-page":"199","article-title":"Serum hormone levels in relation to reproductive and lifestyle factors in postmenopausal women (United States)","volume":"9","author":"Madigan","year":"1998","journal-title":"Cancer Causes Control"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1530\/eje.0.1500161","article-title":"Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: A cross-sectional study in healthy women","volume":"150","author":"Lukanova","year":"2004","journal-title":"Eur. J. Endocrinol."},{"key":"ref_73","first-page":"561","article-title":"C-peptide, IGF-I, sex-steroid hormones and adiposity: A cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)","volume":"16","author":"Bezemer","year":"2005","journal-title":"Cancer Causes Control"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"8623","DOI":"10.1096\/fj.201802347RRR","article-title":"Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model","volume":"33","author":"Morgan","year":"2019","journal-title":"FASEB J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"R30","DOI":"10.1186\/bcr3410","article-title":"HIF-1alpha stimulates aromatase expression driven by prostaglandin E2 in breast adipose stroma","volume":"15","author":"Samarajeewa","year":"2013","journal-title":"Breast Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1210\/en.2018-00529","article-title":"History of Estrogen: Its Purification, Structure, Synthesis, Biologic Actions, and Clinical Implications","volume":"160","author":"Santen","year":"2019","journal-title":"Endocrinology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1089\/wound.2017.0732","article-title":"Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma","volume":"6","author":"Bhattacharyya","year":"2017","journal-title":"Adv. Wound. Care"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e98850","DOI":"10.1172\/jci.insight.98850","article-title":"TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung","volume":"3","author":"Bhattacharyya","year":"2018","journal-title":"JCI Insight"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1007\/BF02814747","article-title":"Mechanisms of cytokine production by fibroblasts-implications for normal connective tissue homeostasis and pathological conditions","volume":"40","author":"Apte","year":"1995","journal-title":"Folia Microbiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"9859","DOI":"10.1038\/s41467-024-52586-x","article-title":"Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis","volume":"15","author":"Faust","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1016\/j.ajpath.2016.06.020","article-title":"Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90","volume":"186","author":"Nazari","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_82","first-page":"1273","article-title":"Distribution of aromatase P450 transcripts and adipose fibroblasts in the human breast","volume":"81","author":"Bulun","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1002\/ijc.34355","article-title":"Advances in \u201cadiponcosis\u201d: Insights in the inner mechanisms at the base of adipose and tumour tissues interplay","volume":"152","author":"Pagano","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s13679-021-00426-0","article-title":"Gender Differences in Obesity-Related Cancers","volume":"10","author":"Argyrakopoulou","year":"2021","journal-title":"Curr. Obes. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s13679-023-00497-1","article-title":"Obesity Paradox: Fact or Fiction?","volume":"12","author":"Simati","year":"2023","journal-title":"Curr. Obes. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1210\/en.2018-00574","article-title":"Diabetes, Obesity, and Breast Cancer","volume":"159","author":"Kang","year":"2018","journal-title":"Endocrinology"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Papakonstantinou, E., Piperigkou, Z., Karamanos, N.K., and Zolota, V. (2022). Altered Adipokine Expression in Tumor Microenvironment Promotes Development of Triple Negative Breast Cancer. Cancers, 14.","DOI":"10.3390\/cancers14174139"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"18376","DOI":"10.1074\/jbc.M112.355164","article-title":"Increased infiltrated macrophages in benign prostatic hyperplasia (BPH): Role of stromal androgen receptor in macrophage-induced prostate stromal cell proliferation","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1158\/0008-5472.CAN-19-3596","article-title":"Infiltrating Mast Cell-Mediated Stimulation of Estrogen Receptor Activity in Breast Cancer Cells Promotes the Luminal Phenotype","volume":"80","author":"Majorini","year":"2020","journal-title":"Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1200\/JCO.2010.29.7614","article-title":"Effect of obesity on prognosis after early-stage breast cancer","volume":"29","author":"Ewertz","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/bjc.2013.367","article-title":"The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: An analysis of the randomised ABCSG-6a trial","volume":"109","author":"Gnant","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e213520","DOI":"10.1001\/jamanetworkopen.2021.3520","article-title":"Association of Obesity with Survival Outcomes in Patients with Cancer: A Systematic Review and Meta-analysis","volume":"4","author":"Petrelli","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.1200\/JCO.2009.27.2021","article-title":"Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: An exploratory analysis from the ATAC trial","volume":"28","author":"Sestak","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_94","unstructured":"(2026, April 29). Alzet Technical Information Manual. Available online: https:\/\/www.alzet.com\/products\/alzet_pumps\/performance\/."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1007\/s00018-020-03660-2","article-title":"Dichotomic role of heparanase in a murine model of metabolic syndrome","volume":"78","author":"Hermano","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1172\/JCI43792","article-title":"Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice","volume":"121","author":"Lerner","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cell.2005.02.034","article-title":"Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1\/CXCL12 secretion","volume":"121","author":"Orimo","year":"2005","journal-title":"Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/978-1-0716-1956-8_10","article-title":"Isolation of Normal and Cancer-Associated Fibroblasts","volume":"2424","author":"Zawieracz","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1200\/JCO.2005.05.4155","article-title":"Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival","volume":"24","author":"Cheang","year":"2006","journal-title":"J. Clin. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4338\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:27:20Z","timestamp":1778819240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4338"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":99,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104338"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104338","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]}}}