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: We then tested whether mutant huntingtin played a role in cell motility, which is a functional marker of EMT. We performed random cell migration assays with PyVT/HdhQ7/Q7 and PyVT/HdhQ111/Q111 primary tumour cells (Fig 4A). Cells expressing polyQ-huntingtin moved faster than the corresponding control cells. We also assessed the directed cell migration capacity of the two cell types using Boyden chamber assays, in which PyVT/HdhQ111/Q111 cells transmigrated faster in response to serum than the PyVT/HdhQ7/Q7 cells (Fig 4B). To compare the invasiveness of PyVT/HdhQ7/Q7 and PyVT/HdhQ111/Q111 cells, we used Boyden chambers containing a layer of ECM proteins on top of the membrane (Fig 4C) and found that PyVT/HdhQ111/Q111 cells were more invasive than PyVT/HdhQ7/Q7 cells. Finally, we assessed cell viability in suspension cultures. PyVT/HdhQ111/Q111 suspension cultures contained more live cells than PyVT/HdhQ7/Q7 suspension cultures as measured by annexin V and propidium iodide (PI) staining and flow cytometric analysis (Fig 4D). In contrast, the percentage of apoptotic and dead cells were lower in the cells that expressed polyQ-huntingtin. Taken together these results show that polyQ-huntingtin expression in cancer cells is associated with enhanced migratory and invasive behaviours, and an elevated resistance to anoikis.
Affiliation: Institut Curie, Paris, France; CNRS UMR 3306, Orsay, France.