Role of HER receptors and heregulins in the development of breast cancer metestases

In the paper attempt was undertaken to present the current directions of knowledge progress of the role of HER receptors and heregulins in the development and progression of breast cancer. There is no doupt that great interst has been aroused by the leading role of HER2/HER3 receptors heterodimer as the main regulator of mitotic signals conducted along the MAPKs pathway and antiapoptic signals conducted along the PI3K pathway in breast cancer. The heterodimer of HER2/HER3 receptors, as demonstrated by numerous recent studies is the main and, as it seems, the only mediator of the complex effects exerted by numerous isoforms of heregulins on the most important processes associated with breast cancer progression, among which worth mentioning are invasiveness, angiogenesis and apoptosis.
In addition to proliferative signals emanating from receptor tyrosine kinase family (RTKs) or their effectors, there is a requirement for a concurrent anti-apoptopic signal for efficient transformation. One important signaling molecule that has been implicated in epithelial cell survival is PI3K. More recently the ability of HER2/HER3 heterodimer to recruit the PI3 kinase in promoting tumor progression by providing cell survival signals has been revealed. In addition to stimulating tumor cell proliferation, HER2 overexpression in cancer cells acts as an antiapoptotic cell survival factor. Down-regulation of HER2 expression induces apoptosis in these cells. Selective inhibitors of the PI3K pathway significantly suppressed the growth of tumor cell lines that overexpress HER2 but not the growth of tumor lines with low HER2 expression. These data indicate that PI3K pathway plays an enhanced role in the growth of HER2 overexpressing breast cancer cells, therefore providing a molecular basis for a selective targeting of this signaling pathway in the treatment of HER2 positive human breast malignancies.
In the paper some recent data that suggest the oncogenic properties of HER1 (EGFR) and HER2 (p185) that may be mediated by stimulation of tumor angiogenesis by up-regulation of vascular endothelial growth factor (VEGF) is also presented.
Considering the established role of urokinase plasminogen activator (uPA) and its receptor (uPAR) in invasion, these proteolitic enzymes can regulate cancer metastasis in addition to growth factors. The recent data concerning the possibility that heregulins use the uPA/uPAR autocrine pathway to transduce their signals, leading to invasion are really very intriguing. Additional support for these data is provided by earlier published studies showing that highly invasive breast cancer cells, which secrete HRGs express very high levels of the uPA/uPAR system.