Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.

Unraveling Biomarker Signatures in Triple-Negative Breast Cancer: A Systematic Review for Targeted Approaches

“…Additionally, the eviction from the nucleus or the silencing of isoform c blocked tumor growth, highlighting the dominant oncogenic potential of isoform c and suggesting both canonical and alternative isoforms of ErbB-2 as therapeutic targets in TNBC [ 25 ]. Another study showed that the use of inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 not only blocked NErbB-2 retrograde transport but also suppressed TNBC growth in vitro, ex vivo, and in vivo, suggesting R2 as a potential novel therapeutic agent for TNBC [ 26 ].…”

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

“…For the B2B1 model, NES-harboring cargoes were distinguished only when RanBP3 abundances were very high (Fig. 6a), allowing us to ignore consideration of ErbB–CRM1 interactions 77, 78 in this setting. Further simplifying the analysis, we found that the sensitivities of monopartite (NLS SV40Tag ) and bipartite (2xNLS Cbp80 ) NLS cargoes were identical except for an offset in N/C ratios from differences in affinity for Imp-α:Imp-β (Supplementary Table 4).…”

Exploring Retrograde Trafficking: Mechanisms and Consequences in Cancer and Disease

“…Furthermore, it has recently been elucidated that in some instances of TNBC, HER2 is localised to the nucleus, where it can drive cancer growth due to its role as a transcription factor [185]. However, Madera et al show that the RT inhibitor, Retro-2, induces an accumulation of HER2 at the plasma membrane or Golgi, depending on the HER2 isoform, resulting in a significant reduction in cell growth [186].…”

“…Retro-2 has emerged as a compound for therapeutically targeting a broad spectrum of RT cargo including bacterial toxins, viruses and RTKs [83,170,186,197,198]. Furthermore, the Retro-2 derivative, Retro-2.1, which is more potent than the parent form, is also being investigated for treatment against herpes simplex virus and polyomavirus in vitro, and more recently in vivo [197][198][199].…”

“…Furthermore, the Retro-2 derivative, Retro-2.1, which is more potent than the parent form, is also being investigated for treatment against herpes simplex virus and polyomavirus in vitro, and more recently in vivo [197][198][199]. Similar to BFA, recent efforts by Vinck et al have aimed to improve the delivery of Retro-2.1 using hydrogels and if coupled with recent evidence by Madera et al Retro-2.1 could prove to have promising applications in cancer therapeutics [186,199].…”