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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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Oncogene-induced mammary tumours develop faster in HD miceTumour-free survival curves of MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7; t50 = 65 ± 1 days; n = 19), MMTV-PyVT/HdhQ7/Q111 (HdhQ7/Q111; t50 = 62 ± 4 days; n = 37) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111; t50 = 52 ± 2 days; n = 25) mice. Kaplan–Meier Analysis, Logrank test: p-value < 0.0001.Whole mount carmine aluminium staining of MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 abdominal mammary glands at 8, 12 and 14 weeks.Percentage of tumoural tissue evaluated on whole mount carmine aluminium staining (at least n = 3 mice per genotype and per time point). At 14 weeks, MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ7/Q111: p-value = 0.0186; MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.0024; MMTV-PyVT/HdhQ7/Q111versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.1558.Hematoxylin and eosin staining of sections from MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks).Immunohistochemical staining of sections from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks) with antibodies against cleaved caspase-3, PCNA and Ki67. The graphs represent the quantitative assessments of the percentage of cleaved caspase-3 (p-value = 0.3583), PCNA (***p-value = 0.0010) and Ki67 (**p-value = 0.0080) positive cells (three tumours per genotype, at least 1000 cells scored per condition). n.s., not significant.
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fig01: Oncogene-induced mammary tumours develop faster in HD miceTumour-free survival curves of MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7; t50 = 65 ± 1 days; n = 19), MMTV-PyVT/HdhQ7/Q111 (HdhQ7/Q111; t50 = 62 ± 4 days; n = 37) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111; t50 = 52 ± 2 days; n = 25) mice. Kaplan–Meier Analysis, Logrank test: p-value < 0.0001.Whole mount carmine aluminium staining of MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 abdominal mammary glands at 8, 12 and 14 weeks.Percentage of tumoural tissue evaluated on whole mount carmine aluminium staining (at least n = 3 mice per genotype and per time point). At 14 weeks, MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ7/Q111: p-value = 0.0186; MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.0024; MMTV-PyVT/HdhQ7/Q111versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.1558.Hematoxylin and eosin staining of sections from MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks).Immunohistochemical staining of sections from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks) with antibodies against cleaved caspase-3, PCNA and Ki67. The graphs represent the quantitative assessments of the percentage of cleaved caspase-3 (p-value = 0.3583), PCNA (***p-value = 0.0010) and Ki67 (**p-value = 0.0080) positive cells (three tumours per genotype, at least 1000 cells scored per condition). n.s., not significant.

Mentions: We then generated mice that express the activated polyomavirus middle T antigen (PyVT) oncogene and polyQ-huntingtin. Expression of PyVT under the control of the mouse mammary tumour virus (MMTV) promoter induces mammary adenocarcinoma formation (Guy et al, 1992). MMTV-PyVT mice were crossed with an HD mouse model, the HdhQ111/Q111 mouse line which carries an abnormal 111 CAG repeat expansion in the huntingtin gene encoding an abnormally expanded polyQ stretch in huntingtin (Wheeler et al, 1999). HD behavioural and motor phenotypes arise much later than PyVT-induced cancer in these mice (Menalled et al, 2009). Compared with MMTV-PyVT mice expressing wild-type huntingtin (MMTV-PyVT/HdhQ7/Q7), tumours appeared earlier in MMTV-PyVT/HdhQ111/Q111 mice (Fig 1A). Heterozygous MMTV-PyVT/HdhQ7/Q111 mice exhibited an intermediate phenotype. Examination of whole-mount mammary glands from virgin female MMTV-PyVT/HdhQ111/Q111 mice at 8, 12 and 14 weeks (Fig 1B) revealed larger mammary adenocarcinomas than in the huntingtin heterozygous condition, themselves larger than those produced in the wild-type background at the same age. From these stainings, we evaluated the tumour progression by determining the percentage of the mammary gland composed of tumoural tissue at different time points (Fig 1C). Tumour progression was increased in MMTV-PyVT/HdhQ111/Q111 mice as compared to MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ7/Q7 mice. These results were further confirmed by haematoxylin and eosin staining analysis (4th mammary gland at 14 weeks of age; Fig 1D). Mammary tumours in the wild-type mice were more differentiated than those in the polyQ situation. In the heterozygous situation, the situation was intermediate.


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)

Oncogene-induced mammary tumours develop faster in HD miceTumour-free survival curves of MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7; t50 = 65 ± 1 days; n = 19), MMTV-PyVT/HdhQ7/Q111 (HdhQ7/Q111; t50 = 62 ± 4 days; n = 37) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111; t50 = 52 ± 2 days; n = 25) mice. Kaplan–Meier Analysis, Logrank test: p-value < 0.0001.Whole mount carmine aluminium staining of MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 abdominal mammary glands at 8, 12 and 14 weeks.Percentage of tumoural tissue evaluated on whole mount carmine aluminium staining (at least n = 3 mice per genotype and per time point). At 14 weeks, MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ7/Q111: p-value = 0.0186; MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.0024; MMTV-PyVT/HdhQ7/Q111versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.1558.Hematoxylin and eosin staining of sections from MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks).Immunohistochemical staining of sections from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks) with antibodies against cleaved caspase-3, PCNA and Ki67. The graphs represent the quantitative assessments of the percentage of cleaved caspase-3 (p-value = 0.3583), PCNA (***p-value = 0.0010) and Ki67 (**p-value = 0.0080) positive cells (three tumours per genotype, at least 1000 cells scored per condition). n.s., not significant.
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fig01: Oncogene-induced mammary tumours develop faster in HD miceTumour-free survival curves of MMTV-PyVT/HdhQ7/Q7 (HdhQ7/Q7; t50 = 65 ± 1 days; n = 19), MMTV-PyVT/HdhQ7/Q111 (HdhQ7/Q111; t50 = 62 ± 4 days; n = 37) and MMTV-PyVT/HdhQ111/Q111 (HdhQ111/Q111; t50 = 52 ± 2 days; n = 25) mice. Kaplan–Meier Analysis, Logrank test: p-value < 0.0001.Whole mount carmine aluminium staining of MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 abdominal mammary glands at 8, 12 and 14 weeks.Percentage of tumoural tissue evaluated on whole mount carmine aluminium staining (at least n = 3 mice per genotype and per time point). At 14 weeks, MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ7/Q111: p-value = 0.0186; MMTV-PyVT/HdhQ7/Q7versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.0024; MMTV-PyVT/HdhQ7/Q111versus MMTV-PyVT/HdhQ111/Q111: p-value = 0.1558.Hematoxylin and eosin staining of sections from MMTV-PyVT/HdhQ7/Q7, MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks).Immunohistochemical staining of sections from MMTV-PyVT/HdhQ7/Q7 and MMTV-PyVT/HdhQ111/Q111 tumours (4th mammary gland, 14 weeks) with antibodies against cleaved caspase-3, PCNA and Ki67. The graphs represent the quantitative assessments of the percentage of cleaved caspase-3 (p-value = 0.3583), PCNA (***p-value = 0.0010) and Ki67 (**p-value = 0.0080) positive cells (three tumours per genotype, at least 1000 cells scored per condition). n.s., not significant.
Mentions: We then generated mice that express the activated polyomavirus middle T antigen (PyVT) oncogene and polyQ-huntingtin. Expression of PyVT under the control of the mouse mammary tumour virus (MMTV) promoter induces mammary adenocarcinoma formation (Guy et al, 1992). MMTV-PyVT mice were crossed with an HD mouse model, the HdhQ111/Q111 mouse line which carries an abnormal 111 CAG repeat expansion in the huntingtin gene encoding an abnormally expanded polyQ stretch in huntingtin (Wheeler et al, 1999). HD behavioural and motor phenotypes arise much later than PyVT-induced cancer in these mice (Menalled et al, 2009). Compared with MMTV-PyVT mice expressing wild-type huntingtin (MMTV-PyVT/HdhQ7/Q7), tumours appeared earlier in MMTV-PyVT/HdhQ111/Q111 mice (Fig 1A). Heterozygous MMTV-PyVT/HdhQ7/Q111 mice exhibited an intermediate phenotype. Examination of whole-mount mammary glands from virgin female MMTV-PyVT/HdhQ111/Q111 mice at 8, 12 and 14 weeks (Fig 1B) revealed larger mammary adenocarcinomas than in the huntingtin heterozygous condition, themselves larger than those produced in the wild-type background at the same age. From these stainings, we evaluated the tumour progression by determining the percentage of the mammary gland composed of tumoural tissue at different time points (Fig 1C). Tumour progression was increased in MMTV-PyVT/HdhQ111/Q111 mice as compared to MMTV-PyVT/HdhQ7/Q111 and MMTV-PyVT/HdhQ7/Q7 mice. These results were further confirmed by haematoxylin and eosin staining analysis (4th mammary gland at 14 weeks of age; Fig 1D). Mammary tumours in the wild-type mice were more differentiated than those in the polyQ situation. In the heterozygous situation, the situation was intermediate.

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