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

  • Nat Commun. 2023 Apr 13;14(1):2110. doi: 10.1038/s41467-023-37914-x.
Lixin Wang  #  1 ,  B Bishal Paudel  #  1 ,  R Anthony McKnight  1  2 ,  Kevin A Janes  3  4
Affiliations
  • 1. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
  • 2. Olympus Veran Technologies, St. Louis, MO, USA.
  • 3. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 4. Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA. [email protected].
  • # Contributed equally.
PMID: 37055441 DOI: 10.1038/s41467-023-37914-x
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.

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