Serum Igf-1 and Nodal Metastasis in Breast Cancer

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 tumourigenesis3. 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 igfbp36. Increased igf signalling has been reported in clinical breast cancer specimens and has been linked to disease progression and recurrence7–9. Furthermore, overexpression of igf-1r has been found in most breast cancer cell lines, including endocrineresponsive MCF-7 human breast cancer cells10,11, which show active crosstalk between the estrogen receptor (er) and igf signalling10,11. 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 cells12,13. 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 ABSTRACT