The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology.
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Date
2011-01-01ICR Author
Author
Eccles, SA
Type
Journal Article
Metadata
Show full item recordAbstract
The EGFR/Erb-B receptor tyrosine kinases each play distinct and complementary roles in normal breast development. The four receptors form both homodimers and heterodimers in response to binding by ligands which show selectivity for one or more of the receptors (except Erb-B2). Together with the additional flexibility generated by the formation of different dimer pairs, these signalling networks play key roles in directing a variety of both autocrine and paracrine cellular responses. Complex two-way interactions between mammary epithelial cells and the surrounding stroma direct proliferation, duct formation, branching and terminal differentiation during puberty, pregnancy and lactation, with each receptor and ligand fulfilling distinct roles. Caricatures of the normal role of EGFR/Erb-B signalling resulting in aberrant cellular responses are seen in breast cancers, where over-expression and/or (less commonly) mutation of one or more of the receptors results in enhanced cell proliferation, motility, release of proteases and angiogenic factors. Given their importance in tumour progression, compared with most normal adult tissues and their links with resistance to chemotherapy and anti-endocrine therapy, Erb-B receptors (most notably Erb-B2) have been exploited as therapeutic targets. Monoclonal antibodies (e.g. trastuzumab, pertuzumab) and small molecule tyrosine kinase inhibitors (e.g. lapatinib, afatinib) have shown significant clinical responses in some breast cancer subtypes. Additional approaches include targeted toxins or drugs, peptide vaccines, immunRNase and chaperone inhibitors to deplete Erb-B2 protein levels. Greater understanding of the full spectrum of Erb-B-mediated signalling pathways and their misregulation in breast cancer will provide additional strategies to control malignant progression.
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Subject
Breast
Animals
Humans
Mice
Rats
Breast Neoplasms
Neoplasm Invasiveness
Neoplasm Metastasis
Neovascularization, Pathologic
Receptor, erbB-2
Oncogene Proteins v-erbB
Ligands
Signal Transduction
Pregnancy
Mutation
Female
Neoplastic Stem Cells
ErbB Receptors
Research team
Tumour Biology & Metastasis
Language
eng
License start date
2011-01
Citation
The International journal of developmental biology, 2011, 55 (7-9), pp. 685 - 696
Publisher
UPV/EHU Press