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Mammary adipocytes promote breast tumor cell invasion and angiogenesis in the context of menopause and obesity.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Oct; Vol. 1870 (7), pp. 167325. Date of Electronic Publication: 2024 Jun 24. - Publication Year :
- 2024
-
Abstract
- The mechanism(s) underlying obesity-related postmenopausal (PM) breast cancer (BC) are not clearly understood. We hypothesized that the increased local presence of 'obese' mammary adipocytes within the BC microenvironment promotes the acquisition of an invasive and angiogenic BC cell phenotype and accelerates tumor proliferation and progression. BC cells, treated with primary mammary adipocyte secretome from premenopausal (Pre-M) and PM obese women (ObAdCM; obese adipocyte conditioned-media) upregulated the expression of several pro-tumorigenic factors including VEGF, lipocalin-2 and IL-6. Both Pre-M and PM ObAdCM stimulated endothelial cell recruitment and proliferation and significantly stimulated BC cell proliferation, migration and invasion. IL-6 and LCN2 induced STAT3/Akt signaling in BC cells and STAT3 inhibition abrogated the ObAdCM-stimulated BC cell proliferation and migration. Expression of proangiogenic regulators including VEGF, NRP1, NRP2, IL8RB, TGFβ2, and TSP-1 were found to be differentially regulated in mammary adipocytes from obese PM women. Comparative RNAseq indicated an upregulation of PI3K/Akt signaling, ECM-receptor interactions and lipid/fatty acid metabolism in PM versus Pre-M mammary adipocytes. Our results demonstrate that irrespective of menopausal status, cross-talk between obese mammary adipocytes and BC cells promotes tumor aggressiveness and suggest that targeting the LCN2/IL-6/STAT3 signaling axis may be a useful strategy in obesity-driven breast tumorigenesis.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Female
Humans
Cell Line, Tumor
Interleukin-6 metabolism
Lipocalin-2 metabolism
Lipocalin-2 genetics
Menopause metabolism
Neoplasm Invasiveness
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
Tumor Microenvironment
Adipocytes metabolism
Adipocytes pathology
Breast Neoplasms pathology
Breast Neoplasms metabolism
Cell Movement
Cell Proliferation
Neovascularization, Pathologic metabolism
Neovascularization, Pathologic pathology
Obesity metabolism
Obesity pathology
STAT3 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1870
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 38925485
- Full Text :
- https://doi.org/10.1016/j.bbadis.2024.167325