Adipocyte-derived exosomes may promote breast cancer progression in type 2 diabetes

Obesity and metabolic diseases, such as insulin resistance and type 2 diabetes (T2D), are associated with metastatic breast cancer in postmenopausal women. Here, we investigated the critical cellular and molecular factors behind this link. We found that primary human adipocytes shed extracellular ve...

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Bibliographic Details
Published in:Science signaling 2021-11, Vol.14 (710), p.eabj2807-eabj2807
Main Authors: Jafari, Naser, Kolla, Manohar, Meshulam, Tova, Shafran, Jordan S, Qiu, Yuhan, Casey, Allison N, Pompa, Isabella R, Ennis, Christina S, Mazzeo, Carla S, Rabhi, Nabil, Farmer, Stephen R, Denis, Gerald V
Format: Article
Language:English
Subjects:
Adipocytes
Body fat
Breast
Breast cancer
Breast Neoplasms
Cargo
Crosstalk
Cytology
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2
Epigenetics
Exosomes
Female
Gene expression
Genes
Humans
Insulin
Insulin resistance
Medical prognosis
Mesenchyme
Metabolic disorders
Metabolism
Metastases
Metastasis
Obesity
Post-menopause
Proteins
Stem cells
Thrombospondin
Transcription
Tumor cell lines
Vesicles
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Summary:Obesity and metabolic diseases, such as insulin resistance and type 2 diabetes (T2D), are associated with metastatic breast cancer in postmenopausal women. Here, we investigated the critical cellular and molecular factors behind this link. We found that primary human adipocytes shed extracellular vesicles, specifically exosomes, that induced the expression of genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem–like cell (CSC) traits in cocultured breast cancer cell lines. Transcription of these genes was further increased in cells exposed to exosomes shed from T2D patient–derived adipocytes or insulin-resistant adipocytes and required the epigenetic reader proteins BRD2 and BRD4 in recipient cells. The thrombospondin family protein TSP5, which is associated with cancer, was more abundant in exosomes from T2D or insulin-resistant adipocytes and partially contributed to EMT in recipient cells. Bioinformatic analysis of breast cancer patient tissue showed that greater coexpression of (which encodes TSP5) and or correlated with poorer prognosis, specifically decreased distant metastasis–free survival. Our findings reveal a mechanism of exosome-mediated cross-talk between metabolically abnormal adipocytes and breast cancer cells that may promote tumor aggressiveness in patients with T2D.
ISSN:1945-0877
1937-9145
DOI:10.1126/SCISIGNAL.ABJ2807