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

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• HER2/ErbB2 activation is linked to breast cancer progression from ductal carcinoma in situ (DCIS).
• The mechanisms behind the incomplete penetrance of the 3D spheroid disruption phenotype by HER2 remain unclear.
• Understanding ErbB protein transport is crucial for deciphering cancer development.

Purpose of the Study:

• To investigate the mechanisms underlying HER2-mediated disruption of breast epithelial cell organization.
• To identify factors influencing the penetrance of the 3D phenotype associated with HER2 activation.
• To elucidate the role of nucleocytoplasmic transport in the transition from premalignant to malignant breast cancer.

Main Methods:

• Utilized inducible HER2/ErbB2-EGFR/ErbB1 heterodimers to study phenotype penetrance.
• Analyzed transcriptomic changes correlated with phenotype expression.
• Developed and employed a systems model of nucleocytoplasmic transport incorporating feedback loops.

Main Results:

• Phenotype penetrance was matched to transcriptomic alterations, revealing karyopherin network reconfiguration.
• Induction of exportin CSE1L reduced nuclear ErbB accumulation; nuclear ErbBs induced miR-205, silencing importin KPNA1.
• Systems modeling showed ultrasensitivity of ErbB localization to CSE1L levels.
• Cse1l deficiency in Erbb2-driven carcinomas led to less irregular outgrowth from mammary ducts.
• HER2 variants with attenuated nuclear localization signals (NLS) promoted escape in 3D culture.

Conclusions:

• Adaptive nucleocytoplasmic relocalization of HER2 functions as a systems-level molecular switch.
• This switch is critical for the premalignant-to-malignant transition in breast cancer.
• Targeting nucleocytoplasmic transport may offer therapeutic strategies for HER2-driven breast cancers.