is activated after ligand binding of insulin, igf-1, or igf-2. Receptor stimulation leads to autophosphorylation of tyrosine residues and drives the activation of downstream signalling pathways, including the mapk (mitogen-activated protein kinase) and pi3k (phosphatidylinositol 3-kinase) cascades, which serve to influence key cell survival and proliferation pathways. The igfs are multifunctional peptides that regulate cell proliferation, differentiation, and apoptosis, which are important in tumourigenesis 3 .Unlike most other growth factors, igf peptides occur in large concentrations in the circulation and have systemic, hormonal, and local paracrine effects on cell behavior. In the circulation, igf-1 binds chiefly to the main igf binding protein, igfbp3. The literature on the relationship between breast cancer risk and circulating concentrations of igf-1 and igfbp3 had indicated an increased risk for women with increased levels of igf-1 and with low levels of igfbp3 6 .Increased igf signalling has been reported in clinical breast cancer specimens and has been linked to disease progression and recurrence 7-9 . Furthermore, overexpression of igf-1r has been found in most breast cancer cell lines, including endocrineresponsive MCF-7 human breast cancer cells 10,11 , which show active crosstalk between the estrogen receptor (er) and igf signalling 10,11 . In that light, estrogens appear to favour synergistic interactions with igfs, resulting in increased expression of igf-1r and growth. Conversely, igfs prime the activation of several kinases that are able to phosphorylate er and initiate gene expression mediated by the estrogen response element. Importantly, the anti-estrogen tamoxifen inhibits igf-1-mediated proliferation in er-positive breast cancer cells 12,13 .Lymph node metastasis is the hallmark of breast cancer progression; it is considered one of the most important prognostic factors. Recent studies have suggested that lymphangiogenesis plays an important
ABSTRACTIncreased insulin-like growth factor (igf) signalling has been observed in breast cancer, including endocrine-responsive cancers, and has been linked to disease progression and recurrence. In particular, igf-1 has the ability to induce and promote lymphangiogenesis through the induction of vascular endothelial growth factor C (vegfc). In the present study, we analyzed serum and tumour samples from 60 patients with endocrine-positive breast cancer to determine the expression and the possible relationship of circulating igf-1, igf binding protein 3 (igfbp3), and vegfc with the presence of lymphatic metastasis and other immunohistochemical parameters. The analysis revealed a clear and significant correlation between high basal levels of igf-1, igfbp3, and vegfc and lymph node metastasis in endocrine-responsive breast cancer. In addition, expression of those molecules was significantly higher in breast cancer patients than in healthy control subjects. Those findings may enable more accurate prediction of prognosis in patients with breast cancer.
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