Hypercholesterolemia Induces Angiogenesis and Accelerates Growth of Breast Tumors In Vivo
Open accessAbstract
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.
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The metabolic changes that occur as a result of diabetes (hyperinsulinemia, hyperglycemia, and dyslipidemia) potentiate signaling pathways and may increase the oncogenic nature of breast tissue through accelerating cell growth and migration, angiogenesis, increasing metastasis, and decreasing the response to chemotherapy.
“The metabolic changes that occur as a result of diabetes (hyperinsulinemia, hyperglycemia, and dyslipidemia) potentiate signaling pathways and may increase the oncogenic nature of breast tissue through accelerating cell growth and migration, angiogenesis, increasing metastasis, and decreasing the response to chemotherapy (158, 244–247).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [244]
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- Authors
- Pelton, K., Coticchia, C. M., Curatolo, A. S., Schaffner, C. P., Zurakowski, D., Solomon, K. R., & Moses, M. A.
- Affiliations
- Boston Children's Hospital (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Solomon, Keith R.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 184
- Issue
- 7
- Pages
- 2099-2110
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC4076468
- OpenAlex
- W2091624467
- Cited by
- 109
- References
- 59
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 14 · 2021: 11 · 2020: 13 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 13 · 2015: 7 · 2014: 1
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA045548)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- hypercholesterolemia, breast cancer, tumor angiogenesis, tumor growth, ezetimibe, high-fat high-cholesterol diet, serum cholesterol, apoptosis, tumor cell proliferation, microvessel density, MDA-MB-231 cells, obesity, metabolic syndrome, cholesterol-lowering drugs
- MeSH terms
- Ezetimibe, Animals, Azetidines, Cholesterol, Cholesterol, Dietary, Female, Humans, Hypercholesterolemia, Mammary Neoplasms, Experimental, Neoplasm Transplantation, Neovascularization, Pathologic, Mice, SCID, Apoptosis, Cell Line, Tumor, Cell Proliferation, Diet, High-Fat
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