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Lactate in breast cancer cells is associated with evasion of hypoxia-induced cell cycle arrest and adverse patient outcome

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Abstract

Tumor hypoxia is a common microenvironmental factor in breast cancers, resulting in stabilization of Hypoxia-Inducible Factor 1 (HIF-1), the master regulator of hypoxic response in cells. Metabolic adaptation by HIF-1 results in inhibition of citric acid cycle, causing accumulation of lactate in large concentrations in hypoxic cancers. Lactate can therefore serve as a secondary microenvironmental factor influencing cellular response to hypoxia. Presence of lactate can alter the hypoxic response of breast cancers in many ways, sometimes in opposite manners. Lactate stabilizes HIF-1 in oxidative condition, as well as destabilizes HIF-1 in hypoxia, increases cellular acidification, and mitigates HIF-1-driven inhibition of cellular respiration. We therefore tested the effect of lactate in MDA-MB-231 under hypoxia, finding that lactate can activate pathways associated with DNA replication, and cell cycling, as well as tissue morphogenesis associated with invasive processes. Using a bioengineered nano-patterned stromal invasion assay, we also confirmed that high lactate and induced HIF-1α gene overexpression can synergistically promote MDA-MB-231 dissemination and stromal trespass. Furthermore, using The Cancer Genome Atlas, we also surprisingly found that lactate in hypoxia promotes gene expression signatures prognosticating low survival in breast cancer patients. Our work documents that lactate accumulation contributes to increased heterogeneity in breast cancer gene expression promoting cancer growth and reducing patient survival.

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Data availability

RNAseq data for this study is deposited in the NCBI Gene Expression Omnibus (GEO) (Accession number: GSE261312).

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Acknowledgements

We thank National Cancer Institute R37CA248161 for funding the research presented in the manuscript.

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National Cancer Institute, 1R37CA248161, Kshitiz

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  1. Yamin Liu and Yasir Suhail have contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT, USA

    Yamin Liu, Yasir Suhail, Ashkan Novin, Aditya Pant &  Kshitiz

  2. Center for Cell Analysis and Modeling, University of Connecticut Health, Farmington, CT, USA

    Yasir Suhail &  Kshitiz

  3. Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Junaid Afzal &  Kshitiz

  4. NEAG Comprehensive Cancer Center, University of Connecticut Health, Farmington, CT, USA

    Aditya Pant &  Kshitiz

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13577_2024_1046_MOESM1_ESM.tif

Supplementary file1 Mcm5 nuclear levels in hypoxia are reversed by lactate. Representative immunofluorescence images of MDA-MB-231 cells showing Mcm5 levels (green), and DAPI (blue) marking nuclei in normoxia, DMOG, hypoxia, as well as hypoxia with lactate, and NH4H2PO4, a weak acid control for lactate. Quantification in Figure 1G. immunofluorescence images of MDA-MB-231 cells showing Mcm5 levels (green), and DAPI (blue) marking nuclei in normoxia, DMOG, hypoxia, as well as hypoxia with lactate, and NH4H2PO4, a weak acid control for lactate. Quantification in Figure 1G. (TIF 5469 KB)

13577_2024_1046_MOESM2_ESM.tif

Supplementary file2 Lactate can reduce hypoxia-induced HIF-1a levels. Representative immunofluorescence images of MDA-MB-231 cells showing HIF-1α levels (green), and DAPI (blue) marking nuclei in normoxia, DMOG, hypoxia, as well as hypoxia with lactate, and NH4H2PO4, a weak acid control for lactate. Quantification in Figure 2C; images also shown in 2B for limited conditions. (TIF 3494 KB)

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Liu, Y., Suhail, Y., Novin, A. et al. Lactate in breast cancer cells is associated with evasion of hypoxia-induced cell cycle arrest and adverse patient outcome. Human Cell 37, 768–781 (2024). https://doi.org/10.1007/s13577-024-01046-1

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