Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) secreted by triple-negative breast cancer promotes tumor microenvironment fibrosis.
Surbhi VermaStephanie Dudics GiagnocavoMeghan C CurtinMenusha ArumugamSandra M Osburn-StakerGuoying WangAaron AtkinsonDavid A NixDavid H LumJames E CoxKeren I HilgendorfPublished in: bioRxiv : the preprint server for biology (2024)
Obesity is a predisposition factor for breast cancer, suggesting a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of ten human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells (ASPC). The screen identified a key adipogenic modulator, Zinc Alpha-2-Glycoprotein (ZAG/AZGP1), secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG in TNBC patients, but not other clinical subtypes of breast cancer, is linked to poor prognosis. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of ASPCs into cancer-associated fibroblasts to support tumorigenesis.
Keyphrases
- poor prognosis
- adipose tissue
- insulin resistance
- breast cancer cells
- long non coding rna
- induced apoptosis
- high fat diet
- end stage renal disease
- cell cycle arrest
- metabolic syndrome
- high fat diet induced
- chronic kidney disease
- type diabetes
- endoplasmic reticulum stress
- peritoneal dialysis
- skeletal muscle
- genome wide
- physical activity
- signaling pathway
- liver fibrosis
- oxide nanoparticles
- gene expression
- transcription factor
- dna methylation
- idiopathic pulmonary fibrosis
- weight gain
- single cell
- extracellular matrix