title: Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis.
abstract: Obesity is one of the most important preventable causes of cancer and the most significant risk factor for breast cancer in postmenopausal women. Compared with lean women, obese women are more likely to be diagnosed with a larger, higher grade tumor, an increased incidence of lymph node metastases, and elevated risk of distant recurrence. However, the mechanisms connecting obesity to the pathogenesis of breast cancer are poorly defined. Here, we show that during obesity, adipocytes within human and mouse breast tissues recruit and activate macrophages through a previously uncharacterized CCL2/IL-1β/CXCL12 signaling pathway. Activated macrophages in turn promote stromal vascularization and angiogenesis even before the formation of cancer. Recapitulating these changes using a novel humanized breast cancer model was sufficient to promote angiogenesis and prime the microenvironment prior to neoplastic transformation for accelerated breast oncogenesis. These findings provide a mechanistic role for adipocytes and macrophages before carcinogenesis that may be critical for prevention and treatment of obesity-related cancer.
authors: Authors' Affiliations: Developmental, Molecular, and Chemical Biology Department, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine; Molecular Oncology Research Institute and Medical Oncology and Department of Pathology, Tufts Medical Center, Boston, Massachusetts; and Departments of Medicine, Duke University, Durham, North Carolina.
authors: Lisa M
authors: LM
authors: Arendt
authors: Jessica
authors: J
authors: McCready
authors: Patricia J
authors: PJ
authors: Keller
authors: Dana D
authors: DD
authors: Baker
authors: Stephen P
authors: SP
authors: Naber
authors: Victoria
authors: V
authors: Seewaldt
authors: Charlotte
authors: C
authors: Kuperwasser
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002417:Cattle; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000166:cytology / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D053583:Interleukin-1beta
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