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Intercellular HIF1α reprograms mammary progenitors and myeloid immune evasion to drive high-risk breast lesions
Irene Bertolini, … , Andrew V. Kossenkov, Dario C. Altieri
Irene Bertolini, … , Andrew V. Kossenkov, Dario C. Altieri
Published March 9, 2023
Citation Information: J Clin Invest. 2023;133(8):e164348. https://doi.org/10.1172/JCI164348.
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Research Article Cell biology Oncology Article has an altmetric score of 4

Intercellular HIF1α reprograms mammary progenitors and myeloid immune evasion to drive high-risk breast lesions

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Abstract

The origin of breast cancer, whether primary or recurrent, is unknown. Here, we show that invasive breast cancer cells exposed to hypoxia release small extracellular vesicles (sEVs) that disrupt the differentiation of normal mammary epithelia, expand stem and luminal progenitor cells, and induce atypical ductal hyperplasia and intraepithelial neoplasia. This was accompanied by systemic immunosuppression with increased myeloid cell release of the alarmin S100A9 and oncogenic traits of epithelial-mesenchymal transition, angiogenesis, and local and disseminated luminal cell invasion in vivo. In the presence of a mammary gland driver oncogene (MMTV-PyMT), hypoxic sEVs accelerated bilateral breast cancer onset and progression. Mechanistically, genetic or pharmacologic targeting of hypoxia-inducible factor-1α (HIF1α) packaged in hypoxic sEVs or homozygous deletion of S100A9 normalized mammary gland differentiation, restored T cell function, and prevented atypical hyperplasia. The transcriptome of sEV-induced mammary gland lesions resembled luminal breast cancer, and detection of HIF1α in plasma circulating sEVs from luminal breast cancer patients correlated with disease recurrence. Therefore, sEV-HIF1α signaling drives both local and systemic mechanisms of mammary gland transformation at high risk for evolution to multifocal breast cancer. This pathway may provide a readily accessible biomarker of luminal breast cancer progression.

Authors

Irene Bertolini, Michela Perego, Yulia Nefedova, Cindy Lin, Andrew Milcarek, Peter Vogel, Jagadish C. Ghosh, Andrew V. Kossenkov, Dario C. Altieri

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Figure 2

sEVHYP regulation of mammary epithelium bioenergetics.

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sEVHYP regulation of mammary epithelium bioenergetics.
(A) Schematic dia...
(A) Schematic diagram of gene pathways upregulated (red) or downregulated (blue) in mammary glands of C57BL/6 female mice injected with sEVHYP by RNA-Seq and Ingenuity Pathway Analysis. Z scores and P values for each modulated gene pathway are indicated. OXPHOS, oxidative phosphorylation. (B and C) Mammary glands harvested 6 weeks after sEV injection were analyzed for UCP-1 expression by IHC (B, representative images) and quantified (C). Red boxes, magnification of indicated areas. Scale bars: 100 μm. Mean ± SD (n = 5). (D) Primary mammary epithelial HC11 cells were incubated with AT3 cell–derived sEVs and analyzed for oxygen consumption rates (OCR) on an Agilent Seahorse flux analyzer. Mean ± SD (n = 3). (E) The conditions were as in D, and the rate of ATP production was quantified. Mean ± SD (n = 3). (F) HC11 cells were incubated with AT3 cell–derived sEVs and analyzed for cell proliferation by direct cell counting. Mean ± SD (n = 3). (G) HC11 cells as in F were analyzed after 3 days by Western blotting. p, phosphorylated. (n = 3.) (H and I) sEV-treated HC11 cells were incubated with vehicle (closed circles), Akt inhibitor MK2206 (1 μM, open squares), or ERK inhibitor PD98059 (10 μM, open triangles) and analyzed for cell proliferation (H) or cell death (I) after 7 days by direct cell counting. Mean ± SD (n = 3). For all panels, numbers correspond to P values by 1-way ANOVA with Tukey’s multiple-comparison test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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