title: Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo.
abstract: Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo.
authors: Department of Urology, Boston Children's Hospital, Boston, Massachusetts.
authors: Kristine
authors: K
authors: Pelton
authors: The Program in Vascular Biology, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.
authors: Christine M
authors: CM
authors: Coticchia
authors: The Program in Vascular Biology, Boston Children's Hospital, Boston, Massachusetts.
authors: Adam S
authors: AS
authors: Curatolo
authors: Department of Microbiology and Biochemistry, Waksman Institute, Rutgers, the State University of New Jersey, New Brunswick, New Jersey.
authors: Carl P
authors: CP
authors: Schaffner
authors: Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts; Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts.
authors: David
authors: D
authors: Zurakowski
authors: Department of Urology, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts; Department of Orthopaedic Surgery, Harvard Medical School, Boston, Massachusetts. Electronic address: marsha.moses@childrens.harvard.edu.
authors: Keith R
authors: KR
authors: Solomon
authors: The Program in Vascular Biology, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.
authors: Marsha A
authors: MA
authors: Moses
mesh_terms: D000818:Animals; D017209:Apoptosis; D001384:Azetidines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*
chemical_list: D001384:Azetidines; D002791:Cholesterol, Dietary; D002784:Cholesterol; D000069438:Ezetimibe