Abstract
In Huntington disease (HD), polyglutamine expansion in the huntingtin protein causes specific neuronal death. The consequences of the presence of mutant huntingtin in other tissues are less well understood. Here we propose that mutant huntingtin influences breast cancer progression. Indeed, we show that mammary tumours appear earlier in mouse breast cancer models expressing mutant huntingtin as compared to control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern that reflects enhanced aggressiveness with the overexpression of genes favouring invasion and metastasis. In agreement, mutant huntingtin accelerates epithelial to mesenchymal transition and enhances cell motility and invasion. Also, lung metastasis is higher in HD conditions than in control mice. 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. Our study may thus have important implications for both cancer and HD.
Highlights
The bulk of interest in the huntingtin protein has centred on the fact that, when mutated, huntingtin causes Huntington’sz disease (HD), a devastating neurodegenerative disorder
Mutant huntingtin is expressed in human breast tumours While research on Huntington disease (HD) has mostly focused on neurological symptoms, we investigated whether breast cancer could be influenced by the expression of mutant huntingtin
We suggest here that the reported huntingtin functions depend on the cell type and the cell context being studied as we found that mutant huntingtin conferred resistance to anoikis to cancer cells while it renders them more sensitive to Trastuzumab treatment
Summary
The bulk of interest in the huntingtin protein has centred on the fact that, when mutated, huntingtin causes Huntington’sz disease (HD), a devastating neurodegenerative disorder. Www.embomolmed.org coated vesicles, endosomal and endoplasmic compartments, mitochondria and microtubules Consistent with this subcellular localization, huntingtin interacts with proteins involved in gene expression, intracellular transport, intracellular signalling and metabolism and appears to be involved in various cellular functions (Harjes & Wanker, 2003; Li & Li, 2004). PolyQ-huntingtin induces death of neurons in the brain via distinct but complementary pathways including deregulation of apoptosis and/or autophagy, altered transcription, metabolism and cellular stress responses (Borrell-Pages et al, 2006; Zuccato et al, 2010). These disturbances were originally mostly attributed to the gain of new toxic functions of polyQ-huntingtin. We propose a link between molecular pathways underlying neurodegeneration, cancer tumourigenesis and metastasis through mutant huntingtin
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