The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling.
Bottom Line: In agreement, mutant huntingtin accelerates epithelial to mesenchymal transition and enhances cell motility and invasion.Finally, we report that in HD, the dynamin dependent endocytosis of the ErbB2/HER2 receptor tyrosine kinase is reduced.This leads to its accumulation and to subsequent increases in cell motility and proliferation.
Affiliation: Institut Curie, Paris, France; CNRS UMR 3306, Orsay, France.Show MeSH
Related in: MedlinePlus
Mentions: How does mutant huntingtin enhance tumour aggressiveness? One possible molecular mechanism underlying the progression from normal breast epithelia to invasive cancer cells involves the accumulation of ErbB receptors (Roepstorff et al, 2008). We evaluated the levels of ErbB2 (rat neu or human HER2) in MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours by immunohistochemistry and found a marked increase of ErbB2 in polyQ-expressing tumours as compared to the control tumours (Fig 5A, left panels). The increase was specifically observed at the plasma membrane as revealed by linescan analysis (Fig 5A, right). Furthermore, it was confirmed by immunoblotting and corresponding quantification (Fig 5B). In heterozygous MMTV-PyVT/HdhQ7/Q111 mice, the accumulation of ErbB2 was intermediate (Supporting Information Fig S4B). We then analysed the levels of total and activated Akt – a well described downstream target of ErbB2 – in control and polyQ-huntingtin tumours. We observed a statistically significant activation of this pathway as detected by the increase in the ratio of the active versus the total level of Akt in MMTV-PyVT/HdhQ111/Q111 compared to MMTV-PyVT/HdhQ7/Q7 tumours (Fig 5B). Thus polyQ-huntingtin leads to ErbB2 accumulation and Akt activation.
Affiliation: Institut Curie, Paris, France; CNRS UMR 3306, Orsay, France.