Search

Breast cancer (BC) is one of the most frequent malignancies in women (Jemal et al, 2008). HER2 overexpressing and/or gene amplified tumours represent approximately 25% of all BC, and they are associated with an aggressive phenotype, metastases, resistance to chemotherapy (CT), and poor prognosis (Slamon et al, 1987, 1989; Peiro et al, 2007; Nguyen et al, 2008). Nevertheless, the outcome has changed dramatically with the introduction of trastuzumab, a humanised monoclonal antibody that targets the HER2 extracellular domain (Murphy and Modi, 2009). It is very effective in combination with CT for the treatment of early stages (Viani et al, 2007) or metastatic BC (Pegram et al, 2004; Brufsky et al, 2005), and even as a single-agent for the later group (Vogel et al, 2002), showing in both groups of patients a substantial decrease in cancer recurrence and mortality (Slamon et al, 2001; Piccart-Gebhart et al, 2005; Joensuu et al, 2006; Untch et al, 2008). Despite its demonstrated clinical benefit, about 30–50% of patients do not respond, and those with metastasis that achieved an initial response to trastuzumab-based regimens will develop drug resistance. Currently, in clinical practice there are not conclusive biomarkers that allow the selection of patients who will respond to trastuzumab and the exact molecular mechanisms are still not well defined. Several growth factor receptors and signalling molecules have been proposed to be responsible for trastuzumab resistance, such as downregulation of the surface HER2 protein by endocytosis and degradation (Austin et al, 2004), p27 downregulation (Lane et al, 2001; Nahta et al, 2004), activation of insulin-like growth factor 1-receptor (IGF1R) (Lu et al, 2001; Nahta et al, 2005), interaction between HER2 and epidermal growth factor 1-receptor (EGFR) (Diermeier et al, 2005), phosphatase and tensin homologue (PTEN) loss (Nagata et al, 2004), phosphoinositide 3-kinase (PI3K)/Akt activation (Esteva et al, 2011; Razis et al, 2011), MUC1 (Fessler et al, 2009) and MUC4 upregulation (Nagy et al, 2005), and the crosstalk with the ER signalling pathway (Slamon et al, 2001). More recently, the non-receptor tyrosine kinase c-SRC (SRC) has been suggested as a potential key modulator of trastuzumab response (Zhang et al, 2011). Therefore, the aim of our study was to evaluate the relevance of alterations in the PI3K/Akt/mTOR and Ras/mitogen-activated protein kinase (MAPK) signalling pathways, given their role in cell cycle progression. We performed an extensive immunohistochemical and molecular analysis of several biological markers related with these pathways, in a series of patients with HER2-positive BC in stage I-IV, to determine their prognostic relevance, and as a result, their potential involvement in the mechanisms of response to trastuzumab.