INTERCELLULAR HIF1alpha REPROGAMS MAMMARY PROGENITORS AND MYELOID IMMUNE EVASION TO DRIVE HIGH-RISK BREAST LESIONS

ABSTRACT: The origin of breast cancer, whether primary or recurrent,is unknown. Here, we show that invasive breast cancer cells under conditions of hypoxia release small extracellular vesicles (sEV) that disrupt the differentiation hierarchy of the normal mammary epithelium, expand stem and luminal progenitor cells, and induce atypical ductal hyperplasia, cellular proliferation, and intraepithelial neoplasia. This is accompanied by systemic immunosuppression with increased myeloid cell release of the “alarmin”, S100A9, and multiple oncogenic traits of EMT, sustained angiogenesis, and local and disseminated luminal cell invasion, in vivo. When applied on the genetic background of a driver oncogene (MMTV-PyMT), hypoxic sEV accelerate bilateral breast cancer onset and progression. Mechanistically, genetic or pharmacologic targeting of hypoxia-inducible factor-1 (HIF1) packaged in hypoxic sEV or homozygous deletion of S100A9 normalizes mammary gland differentiation, restores T cell function and prevents atypical hyperplasia. The transcriptome of sEV-induced mammary gland lesions resembles luminal breast cancer, and detection of HIF1 in plasma circulating sEV from luminal breast cancer patients correlates with clinical recurrence. Therefore, a pleiotropic sEV-HIF1 signaling axis drives local and systemic mechanisms of mammary gland transformation at high risk for full-blown, multifocal breast cancer. This pathway may provide a readily accessible biomarker of luminal breast cancer progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE225986 | GEO | 2023/05/12

REPOSITORIES: GEO