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Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis

ABSTRACT: Obesity is predicted to become the largest modifiable risk factor for breast cancer in postmenopausal women, yet the mechanisms underlying this association are unclear. We identified a novel protective mechanism for lean adipocytes to suppress breast cancer by secreting the oxylipin 9S-HODE, which induces ferroptosis in breast cancer cells while sparing normal breast epithelial cells. Consequently, the inhibition of ferroptosis accelerates breast cancer in lean, but not obese, mice. Obese adipocytes fail to secrete 9S-HODE, suggesting that the loss of 9S-HODE significantly contributes to the acceleration of breast cancer in obesity. Further, 9S-HODE supplementation into tumors in obese mice is sufficient to reduce tumor burden and additionally can inhibit the growth of patient-derived breast cancer organoids, underscoring its potential as a therapeutic agent.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE300839 | GEO | 2025/08/20

REPOSITORIES: GEO

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Project description:Background Understanding how obesity impacts human mammary adipose tissue (MAT) biology is crucial for deciphering its role in mammary epithelium during both physiological and pathophysiological processes, including breast cancer. Hypertrophic mammary adipocytes and Crown-like Structures are present in MAT of obese patients but whether these changes initiate a fibro-inflammatory response at the tissue level remains insufficiently explored. Objective We aimed to investigate the markers of adipose tissue dysfunction (immune cell infiltration, secretion pattern and fibrosis) in tumor-free MAT of obese versus lean patients Methods Tumor-free MAT were obtained from 61 lean and obese women who underwent mastectomy for breast cancer risk reduction or treatment. Immune and non-immune cell infiltration was determined using flow cytometry. Bulk transcriptomic was used to characterize the phenotype of CD206+ macrophages whose infiltration is increased in obese. Conditioned-medium were prepared from MAT to characterize their secretome and dose adipokines and cytokines by ELISA assay. The extra-cellular matrix (ECM) deposition was evaluated by Masson trichrome staining on cross-stained sections and 3D imaging of red picrosirius-stained tissues. Results We observed an increase in CD206+/HLA-DR+ macrophages in the stromal vascular fraction of MAT from obese patients compared to lean ones. Other immune cell infiltration and endothelial or adipose progenitor cell numbers were similar between groups. Bulk transcriptomics on CD206+ macrophages revealed a significant decrease in ECM component secretion and processing in obese samples. Additionally, no heightened secretion of pro-inflammatory cytokines or MCP-1 was noted in obese samples. ECM characterization indicated an absence of fibrosis, with obese MAT showing reduced collagen secretion and deposition compared to lean counterparts. Conclusions Obesity does not associate with inflammation or fibrosis in MAT, underscoring its unique behavior.

Project description:The expression of adipogenic genes is decreased in obesity and diabetes mellitus ; Samuel T. Nadler*, Jonathan P. Stoehr*, Kathryn L. Schueler*, Gene Tanimoto, Brian S. Yandell, and Alan D. Attie*,Â§ ; Departments of * Biochemistry, and Statistics and Horticulture, University of Wisconsin, Madison, WI, 53706; and Affymetrix, Inc., Santa Clara, CA 95051 ; Communicated by Neal L. First, University of Wisconsin, Madison, WI, July 13, 2000 (received for review April 3, 2000) ; Obesity is strongly correlated with type 2 diabetes mellitus, a common disorder of glucose and lipid metabolism. Although adipocytes are critical in obesity, their role in diabetes has only recently been appreciated. We conducted studies by using DNA microarrays to identify differences in gene expression in adipose tissue from lean, obese, and obese-diabetic mice. The expression level of over 11,000 transcripts was analyzed, and 214 transcripts showed significant differences between lean and obese mice. Surprisingly, the expression of genes normally associated with adipocyte differentiation were down-regulated in obesity. Not all obese individuals will become diabetic; many remain normoglycemic despite profound obesity. Understanding the transition to obesity with concomitant diabetes will provide important clues to the pathogenesis of type 2 diabetes. Therefore, we examined the levels of gene expression in adipose tissue from five groups of obese mice with varying degrees of hyperglycemia, and we identified 88 genes whose expression strongly correlated with diabetes severity. This group included many genes that are known to be involved in signal transduction and energy metabolism as well as genes not previously examined in the context of diabetes. Our data show that a decrease in expression of genes normally involved in adipogenesis is associated with obesity, and we further identify genes important for subsequent development of type 2 diabetes mellitus. Experiment Overall Design: For obesity study, lean samples include C57BL/6J lean, (C57BL/6J X BTBR) F1 and BTBR lean, obese sampples incluse C57BL/6J-ob/ob, (C57BL/6J X BTBR) F2-ob/ob and BTBR-ob/ob. All samples are subjected to Mu11K A and B arrays. Experiment Overall Design: For diabetes study, B6-ob/ob, (C57BL/6J X BTBR) F2-ob/ob low glucose, (C57BL/6J X BTBR) F2-ob/ob medium glucose, (C57BL/6J X BTBR) F2-ob/ob high glucose, and BTBR-ob/ob samples were analyzed for genes whose expression levels changes correlated with the plasma glucose levels in these mice. All samples are subjected to Mu11K A and B arrays.

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Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis

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