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Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors

Oncogene volume 40, pages 5651–5664 (2021)Cite this article

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Abstract

Metastatic breast cancer causes most breast cancer-associated deaths, especially in triple negative breast cancers (TNBC). The metastatic drivers of TNBCs are still poorly understood, and effective treatment non-existent. Here we reveal that the presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia-Inducible Factor-1) signaling. Nuclear AURKA activates transcription of “hypoxia-induced genes” under normoxic conditions (pseudohypoxia) and without upregulation of oxygen-sensitive HIF1A subunit. We uncover that AURKA preferentially binds to HIF1B and co-localizes with the HIF complex on DNA. The mass-spectrometry analysis of the AURKA complex further confirmed the presence of CBP and p300 along with other TFIIB/RNApol II components. Importantly, the expression of multiple HIF-dependent genes induced by nuclear AURKA (N-AURKA), including migration/invasion, survival/death, and stemness, promote early cancer dissemination. These results indicate that nuclear, but not cytoplasmic, AURKA is a novel driver of early metastasis. Analysis of clinical tumor specimens revealed a correlation between N-AURKA presence and decreased patient survival. Our results establish a mechanistic link between two critical pathways in cancer metastasis, identifying nuclear AURKA as a crucial upstream regulator of the HIF1 transcription complex and a target for anti-metastatic therapy.

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Fig. 1: Nuclear AURKA positivity correlates with metastasis and more aggressive breast cancer subtypes.
Fig. 2: N-AURKA drives cancer migration/invasion but does not affect proliferation.
Fig. 3: N-AURKA induces hypoxia in xenograft models of breast cancer.
Fig. 4: N-AURKA expressing tumors are highly metastatic.
Fig. 5: RNA-seq profile of N-AURKA cells.
Fig. 6: N-AURKA binds to HIF1A/B and promotes transactivation of hypoxia-response genes.
Fig. 7: HIF1A/B is required for N-AURKA-driven invasion.
Fig. 8: Inhibition of N-AURKA kinase activity decreases breast cancer metastasis.

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Acknowledgements

We thank WVU HSC Office of Graduate Research and Education for outstanding administrative support, WVU Tissue Bank, Genetic Tumor Modeling Core, and Animal Models & Imaging Facilities, supported by the WVUCI and NIH grants P20 RR016440, P30 RR032138/GM103488, and S10RR026378. Flow Cytometry Facility was supported by NIH grants P30GM103488, P30RR032138, and RCP1101809. Bioinformatics Core by NIH grants P20GM103434 and U54 GM-104942. This work was supported by a grant from NIH-NCI CA148671 to ENP. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number CA148671 (to ENP). Small animal imaging and cell image analysis were performed in the West Virginia University Animal Models & Imaging Facility, supported by NIH grants P20RR016440, P30GM103488, U54GM104942, P20GM103434, and S10RR026378. The flow cytometry analysis was done in WVU Flow Cytometry & Single Cell Core Facility, supported by NIH grants GM121322, GM104942, GM103434, and OD016165. The genetic tumor modeling (GTM) core facility provided animal models supported by NIH grant GM121322. The WVU Bioinformatics Core Facility supported by NIH grants P20GM103434 and U54 GM-104942 assisted with RNA-Seq data analysis and interpretation.

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Authors and Affiliations

  1. Department of Biochemistry, West Virginia University, Morgantown, WV, USA

    Kristina M. Whately, Maria A. Voronkova, Abha Maskey, Juergen Loskutov, Hyeran Choi, Sila Yanardag, Naira V. Margaryan, Marc L. Purazo & Elena N. Pugacheva

  2. WVU Cancer Institute, School of Medicine, West Virginia University, Morgantown, WV, USA

    Kristina M. Whately, Maria A. Voronkova, Abha Maskey, Juergen Loskutov, Sila Yanardag, Sijin Wen, Marc L. Purazo, Gangqing Hu & Elena N. Pugacheva

  3. Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV, USA

    Jasleen Gandhi & Gangqing Hu

  4. Department of Medicine, Division of Preventive Medicine, UAB Comprehensive Cancer Center, Birmingham, AL, USA

    Dongquan Chen

  5. Department of Biostatistics, School of Public Health, West Virginia University, Morgantown, WV, USA

    Sijin Wen

  6. Department of Pathology, West Virginia University, Morgantown, WV, USA

    Matthew B. Smolkin

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Contributions

KMW and ENP conceived the project and wrote the manuscript. TMA statistical analysis was performed by ENP. Animal pathology and tumor analysis was done by MSS and KMW. Bioinformatics analysis was performed by DC, GH, JG, and KMW. All remaining experiments and data analysis were performed by KMW, AM, MAV, JL, HC, SY, NVM, SW, MLP and ENP.

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Correspondence to Elena N. Pugacheva.

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Whately, K.M., Voronkova, M.A., Maskey, A. et al. Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors. Oncogene 40, 5651–5664 (2021). https://doi.org/10.1038/s41388-021-01969-1

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