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Nucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state

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  • Lixin Wang

    (University of Virginia)

  • B. Bishal Paudel

    (University of Virginia)

  • R. Anthony McKnight

    (University of Virginia
    Olympus Veran Technologies)

  • Kevin A. Janes

    (University of Virginia
    University of Virginia)

Abstract

Activation of HER2/ErbB2 coincides with escape from ductal carcinoma in situ (DCIS) premalignancy and disrupts 3D organization of cultured breast-epithelial spheroids. The 3D phenotype is infrequent, however, and mechanisms for its incomplete penetrance have been elusive. Using inducible HER2/ErbB2–EGFR/ErbB1 heterodimers, we match phenotype penetrance to the frequency of co-occurring transcriptomic changes and uncover a reconfiguration in the karyopherin network regulating ErbB nucleocytoplasmic transport. Induction of the exportin CSE1L inhibits nuclear accumulation of ErbBs, whereas nuclear ErbBs silence the importin KPNA1 by inducing miR-205. When these negative feedbacks are incorporated into a validated systems model of nucleocytoplasmic transport, steady-state localization of ErbB cargo becomes ultrasensitive to initial CSE1L abundance. Erbb2-driven carcinomas with Cse1l deficiency outgrow less irregularly from mammary ducts, and NLS-attenuating mutants or variants of HER2 favor escape in 3D culture. We conclude here that adaptive nucleocytoplasmic relocalization of HER2 creates a systems-level molecular switch at the premalignant-to-malignant transition.

Suggested Citation

  • Lixin Wang & B. Bishal Paudel & R. Anthony McKnight & Kevin A. Janes, 2023. "Nucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37914-x
    DOI: 10.1038/s41467-023-37914-x
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    References listed on IDEAS

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    1. Arjun Raj & Scott A. Rifkin & Erik Andersen & Alexander van Oudenaarden, 2010. "Variability in gene expression underlies incomplete penetrance," Nature, Nature, vol. 463(7283), pages 913-918, February.
    2. Kathryn Miller-Jensen & Kevin A. Janes & Joan S. Brugge & Douglas A. Lauffenburger, 2007. "Common effector processing mediates cell-specific responses to stimuli," Nature, Nature, vol. 448(7153), pages 604-608, August.
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