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The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling.

Moreira Sousa C, McGuire JR, Thion MS, Gentien D, de la Grange P, Tezenas du Montcel S, Vincent-Salomon A, Durr A, Humbert S - EMBO Mol Med (2013)

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.

View Article: PubMed Central - PubMed

Affiliation: Institut Curie, Paris, France; CNRS UMR 3306, Orsay, France.

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PolyQ-huntingtin promotes membrane ErbB2/HER2 accumulation and sustained signallingImmunostaining of sections from MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111) tumours (originating from the 3rd mammary gland, 14 weeks) for the presence of ErbB2. Representative linescan analysis of the distribution of ErbB2 in wild-type and polyQ-huntingtin expressing cells within the tumour sections are shown.Immunoblotting of total extracts from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (originating from the 3rd mammary gland, 14 weeks) for ErbB2, phosphorylated Akt at serine 473 (Akt(S473)), total Akt and α-tubulin (at least n = 5 tumours per genotype, two independent immunoblotting; ErbB2/tubulin: **p-value = 0.0057; Akt(S473)/Akt: *p-value = 0.0328).mRNA levels of ErbB2 in MMTV-PyVT/HdhQ7/Q7 (n = 4) and MMTV-PyVT/HdhQ111/Q111 (n = 3) tumours as determined by quantitative PCR analysis (p-value = 0.7441; n.s., not significant).
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fig05: PolyQ-huntingtin promotes membrane ErbB2/HER2 accumulation and sustained signallingImmunostaining of sections from MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111) tumours (originating from the 3rd mammary gland, 14 weeks) for the presence of ErbB2. Representative linescan analysis of the distribution of ErbB2 in wild-type and polyQ-huntingtin expressing cells within the tumour sections are shown.Immunoblotting of total extracts from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (originating from the 3rd mammary gland, 14 weeks) for ErbB2, phosphorylated Akt at serine 473 (Akt(S473)), total Akt and α-tubulin (at least n = 5 tumours per genotype, two independent immunoblotting; ErbB2/tubulin: **p-value = 0.0057; Akt(S473)/Akt: *p-value = 0.0328).mRNA levels of ErbB2 in MMTV-PyVT/HdhQ7/Q7 (n = 4) and MMTV-PyVT/HdhQ111/Q111 (n = 3) tumours as determined by quantitative PCR analysis (p-value = 0.7441; n.s., not significant).

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.


The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling.

Moreira Sousa C, McGuire JR, Thion MS, Gentien D, de la Grange P, Tezenas du Montcel S, Vincent-Salomon A, Durr A, Humbert S - EMBO Mol Med (2013)

PolyQ-huntingtin promotes membrane ErbB2/HER2 accumulation and sustained signallingImmunostaining of sections from MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111) tumours (originating from the 3rd mammary gland, 14 weeks) for the presence of ErbB2. Representative linescan analysis of the distribution of ErbB2 in wild-type and polyQ-huntingtin expressing cells within the tumour sections are shown.Immunoblotting of total extracts from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (originating from the 3rd mammary gland, 14 weeks) for ErbB2, phosphorylated Akt at serine 473 (Akt(S473)), total Akt and α-tubulin (at least n = 5 tumours per genotype, two independent immunoblotting; ErbB2/tubulin: **p-value = 0.0057; Akt(S473)/Akt: *p-value = 0.0328).mRNA levels of ErbB2 in MMTV-PyVT/HdhQ7/Q7 (n = 4) and MMTV-PyVT/HdhQ111/Q111 (n = 3) tumours as determined by quantitative PCR analysis (p-value = 0.7441; n.s., not significant).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3569645&req=5

fig05: PolyQ-huntingtin promotes membrane ErbB2/HER2 accumulation and sustained signallingImmunostaining of sections from MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111) tumours (originating from the 3rd mammary gland, 14 weeks) for the presence of ErbB2. Representative linescan analysis of the distribution of ErbB2 in wild-type and polyQ-huntingtin expressing cells within the tumour sections are shown.Immunoblotting of total extracts from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (originating from the 3rd mammary gland, 14 weeks) for ErbB2, phosphorylated Akt at serine 473 (Akt(S473)), total Akt and α-tubulin (at least n = 5 tumours per genotype, two independent immunoblotting; ErbB2/tubulin: **p-value = 0.0057; Akt(S473)/Akt: *p-value = 0.0328).mRNA levels of ErbB2 in MMTV-PyVT/HdhQ7/Q7 (n = 4) and MMTV-PyVT/HdhQ111/Q111 (n = 3) tumours as determined by quantitative PCR analysis (p-value = 0.7441; n.s., not significant).
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Institut Curie, Paris, France; CNRS UMR 3306, Orsay, France.

Show MeSH
Related in: MedlinePlus