Format

Send to

Choose Destination
Am J Pathol. 2014 Jul;184(7):2099-110. doi: 10.1016/j.ajpath.2014.03.006.

Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo.

Author information

1
Department of Urology, Boston Children's Hospital, Boston, Massachusetts.
2
The Program in Vascular Biology, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.
3
The Program in Vascular Biology, Boston Children's Hospital, Boston, Massachusetts.
4
Department of Microbiology and Biochemistry, Waksman Institute, Rutgers, the State University of New Jersey, New Brunswick, New Jersey.
5
Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts; Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts.
6
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.

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.

PMID:
24952430
PMCID:
PMC4076468
DOI:
10.1016/j.ajpath.2014.03.006
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center