Escape from the HER2-activated DCIS-like state is skewed by divergent nucleocytoplasmic transport

Activation of ErbB receptors--HER2/ErbB2 and EGFR/ErbB1--disrupts 3D multicellular organization of breast-epithelial cells with characteristics resembling premalignant escape from ductal carcinoma in situ (DCIS). However, the escape phenotype is infrequent, and a mechanism for its incomplete penetrance has been elusive. By matching phenotype penetrance to the frequency of transcriptomic fluctuations that co-occur, we uncovered a karyopherin network regulating nucleocytoplasmic transport of ErbBs. The exportin CSE1L is sporadically induced and inhibits nuclear accumulation of ErbBs. Separately, nuclear ErbBs upregulate miR-205 to repress protein abundance of the importin KPNA1. When these feedbacks are incorporated into a validated systems model of nucleocytoplasmic transport, steady-state localization of ErbB cargo becomes ultrasensitive to the concentration of CSE1L. Variations or cancer-associated mutations in the NLS-like sequence of HER2 weaken transport and favor the escape phenotype in 3D culture. In vivo, knockdown of Cse1l attenuates the irregular outgrowth of Erbb2-activated mammary carcinomas, suggesting future therapeutic potential. ### Competing Interest Statement The authors have declared no competing interest.