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Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance.

Jackson C, Browell D, Gautrey H, Tyson-Capper A - Int J Cell Biol (2013)

Bottom Line: Overexpression of human epidermal growth factor receptor (HER-2) occurs in 20-30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin.Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology.For example, the splice variant Δ16HER-2 (results from exon 16 skipping) increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention) and p100 (results from intron 15 retention) inhibit tumour cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

ABSTRACT
Overexpression of human epidermal growth factor receptor (HER-2) occurs in 20-30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant Δ16HER-2 (results from exon 16 skipping) increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention) and p100 (results from intron 15 retention) inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. "Individualised" strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

No MeSH data available.


Related in: MedlinePlus

Schematic of HER-2 structure, activation, and signalling. (a) HER-2 is a single transmembrane cell surface receptor with extracellular, transmembrane, and intracellular regions. The extracellular region comprises of two ligand-binding domains (L I and L II) and two cysteine-rich domains (C I and C II) [8]. Intracellularly, HER-2 receptors have intrinsic tyrosine kinase activity (TK). (b) HER-2 does not bind ligands but is activated by forming heterodimers with other ErbB receptors via interaction at the cysteine-rich domains. This results in autophosphorylation of the tyrosine kinase domains and induction of downstream signalling. Normal signalling includes stimulation of the PI3K/AKT pathway which induces survival mechanisms and inhibits apoptosis, whilst the RAS/RAF/MEK/MAPK pathway stimulates cell proliferation [8].
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fig2: Schematic of HER-2 structure, activation, and signalling. (a) HER-2 is a single transmembrane cell surface receptor with extracellular, transmembrane, and intracellular regions. The extracellular region comprises of two ligand-binding domains (L I and L II) and two cysteine-rich domains (C I and C II) [8]. Intracellularly, HER-2 receptors have intrinsic tyrosine kinase activity (TK). (b) HER-2 does not bind ligands but is activated by forming heterodimers with other ErbB receptors via interaction at the cysteine-rich domains. This results in autophosphorylation of the tyrosine kinase domains and induction of downstream signalling. Normal signalling includes stimulation of the PI3K/AKT pathway which induces survival mechanisms and inhibits apoptosis, whilst the RAS/RAF/MEK/MAPK pathway stimulates cell proliferation [8].

Mentions: HER-2 is a 185 kDa transmembrane cell surface receptor of the human epidermal growth factor (EGF) family [6]. There are four receptor members of this family: HER-1 (EGFR, ErbB-1), HER-2 (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4). EGF receptors have a highly conserved extracellular domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity [7] (Figure 2). Ligand-receptor binding induces conformational changes and receptor dimerisation via interaction at both extracellular cysteine-rich regions [7, 8]. This results in autophosphorylation and kinase activation [8]. EGF receptor signalling has important roles in cell proliferation, differentiation, and survival [9] (Figure 2).


Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance.

Jackson C, Browell D, Gautrey H, Tyson-Capper A - Int J Cell Biol (2013)

Schematic of HER-2 structure, activation, and signalling. (a) HER-2 is a single transmembrane cell surface receptor with extracellular, transmembrane, and intracellular regions. The extracellular region comprises of two ligand-binding domains (L I and L II) and two cysteine-rich domains (C I and C II) [8]. Intracellularly, HER-2 receptors have intrinsic tyrosine kinase activity (TK). (b) HER-2 does not bind ligands but is activated by forming heterodimers with other ErbB receptors via interaction at the cysteine-rich domains. This results in autophosphorylation of the tyrosine kinase domains and induction of downstream signalling. Normal signalling includes stimulation of the PI3K/AKT pathway which induces survival mechanisms and inhibits apoptosis, whilst the RAS/RAF/MEK/MAPK pathway stimulates cell proliferation [8].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3713377&req=5

fig2: Schematic of HER-2 structure, activation, and signalling. (a) HER-2 is a single transmembrane cell surface receptor with extracellular, transmembrane, and intracellular regions. The extracellular region comprises of two ligand-binding domains (L I and L II) and two cysteine-rich domains (C I and C II) [8]. Intracellularly, HER-2 receptors have intrinsic tyrosine kinase activity (TK). (b) HER-2 does not bind ligands but is activated by forming heterodimers with other ErbB receptors via interaction at the cysteine-rich domains. This results in autophosphorylation of the tyrosine kinase domains and induction of downstream signalling. Normal signalling includes stimulation of the PI3K/AKT pathway which induces survival mechanisms and inhibits apoptosis, whilst the RAS/RAF/MEK/MAPK pathway stimulates cell proliferation [8].
Mentions: HER-2 is a 185 kDa transmembrane cell surface receptor of the human epidermal growth factor (EGF) family [6]. There are four receptor members of this family: HER-1 (EGFR, ErbB-1), HER-2 (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4). EGF receptors have a highly conserved extracellular domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity [7] (Figure 2). Ligand-receptor binding induces conformational changes and receptor dimerisation via interaction at both extracellular cysteine-rich regions [7, 8]. This results in autophosphorylation and kinase activation [8]. EGF receptor signalling has important roles in cell proliferation, differentiation, and survival [9] (Figure 2).

Bottom Line: Overexpression of human epidermal growth factor receptor (HER-2) occurs in 20-30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin.Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology.For example, the splice variant Δ16HER-2 (results from exon 16 skipping) increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention) and p100 (results from intron 15 retention) inhibit tumour cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

ABSTRACT
Overexpression of human epidermal growth factor receptor (HER-2) occurs in 20-30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant Δ16HER-2 (results from exon 16 skipping) increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention) and p100 (results from intron 15 retention) inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. "Individualised" strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

No MeSH data available.


Related in: MedlinePlus