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Cited by 43Extracellular vesicles in diseaseCancer, Lipids, and MetabolismCaveolin-1 and cellular processes

The Cholesterol Metabolite 27HC Increases Secretion of Extracellular Vesicles Which Promote Breast Cancer Progression

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Baek, Amy E, Krawczynska, Natalia, Das Gupta, Anasuya, Dvoretskiy, Svyatoslav Victorovich, You, Sixian, Park, Jaena, Deng, Yu-Heng, Sorrells, Janet E +11 more·2021·Endocrinology
DOI 10.1210/endocr/bqab095PMC PMC8197285
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Abstract

Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite 27-hydroxycholesterol (27HC) as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and as a liver X receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells with neutrophils (polymorphonuclear neutrophils; PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that includes exosomes. The resulting EVs had a size distribution that was skewed slightly larger than EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across 3 different subtypes: primary murine PMNs, RAW264.7 monocytic cells, and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in 2 different syngeneic models, demonstrating the potential role of 27HC-induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages, and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their protumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV-treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively, however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.

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  • 27-hydroxycholesterol works through liver x receptors in myeloid immune cells to suppress T cell proliferation and function, stimulate secretion of pro-tumor extracellular vesicles, and promote tumor and metastatic growth.

    “An oxysterol metabolite of cholesterol, 27-hydroxycholesterol, was found to work through the liver x receptors in myeloid immune cells to robustly suppress T cell proliferation and function, and stimulate the secretion of pro-tumor extracellular vesicles, ultimately promoting the growth of tumors and metastatic lesions (17, 20–23).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [20]

    The Abstract reports that 27HC acts through LXRs in myeloid cells to suppress anticancer T-cell activity, while the Results and Discussion report increased EV secretion and tumor growth and metastasis from 27HC-induced EVs. The Discussion says the mechanism by which 27HC stimulates EV secretion remains to be determined, so the paper does not establish that LXR signaling mediates that secretion. Page numbers are not available in our copy. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Baek, A. E., Krawczynska, N., Das Gupta, A., Dvoretskiy, S. V., You, S., Park, J., Deng, Y.-H., Sorrells, J. E., Smith, B. P., Ma, L., Nelson, A. T., McDowell, H. B., Sprenger, A., Henn, M. A., Madak-Erdogan, Z., Kong, H., Boppart, S. A., Boppart, M. D., & Nelson, E. R.
Affiliations
  • University of Illinois Urbana-Champaign (US)
  • Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
  • Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
Corresponding author
  • Baek, Amy E
  • Nelson, Erik R
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2021-05-06
Volume
162
Issue
7
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endocr/bqab095
PMC
PMC8197285
OpenAlex
W3159273125
Cited by
43
References
0
Citations by year
2026: 6 · 2025: 13 · 2024: 5 · 2023: 4 · 2022: 12 · 2021: 3
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute
  • National Institutes of Health (R01CA234025, R01CA241618)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (R01AR072735)
  • Alzheimer’s Association (2019-AARG-NTF-644507)
  • American Institute of Cancer Research (579732)
  • Department of Defense Breast Cancer Research (BC171214, BC200206)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords
27-hydroxycholesterol, cholesterol metabolites, extracellular vesicles, breast cancer progression, neutrophils, myeloid cells, metastasis, exosomes, tumor microenvironment, tumor growth, liver X receptor, estrogen receptor modulation
MeSH terms
Extracellular Vesicles, RAW 264.7 Cells, Animals, Female, Hydroxycholesterols, Hypercholesterolemia, Mammary Neoplasms, Experimental, Neoplasm Metastasis, Neoplasm Transplantation, Neutrophils, Disease Progression, Estrogen Receptor Modulators, Cell Line, Tumor, Mice

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