AbstractsBiology & Animal Science

The phosphatidylinositol 3' kinase (PI3K)/Akt signalling pathway is activated in several human cancers. PI3K signalling is enhanced by mutations in the p110alpha isoform of PI3K or through loss of negative regulators such as the tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). This proto-oncogenic pathway can also be induced in cancer downstream of activated receptor tyrosine kinases such as HER2/ErbB2, which is overexpressed in 30% of breast cancers. In fact, PI3K pathway activation in breast cancer has been associated with resistance to HER2-targeted therapies. In this thesis, we have used transgenic mouse models to investigate the importance of PI3K signalling in ErbB2-mediated mammary tumourigenesis.Our laboratory has previously shown that mammary-specific deletion of Pten can accelerate mammary tumour initiation and metastasis driven by endogenous expression of activated ErbB2. Here, we have validated these findings by demonstrating that Pten loss can cooperate with transgenic overexpression of activated ErbB2 during mammary tumour progression. We have also showed that expression of a constitutively activated p110alpha transgene in the mammary epithelium can enhance the metastatic potential of ErbB2-induced tumours. Conversely, it seems that disruption of PI3K signalling can impair transformation in the mammary gland. We have demonstrated that genetic ablation of p110alpha dramatically delays mammary tumour onset and impairs pulmonary metastasis in mammary tumour models induced by either activated ErbB2 or by the viral oncogene polyomavirus middle T antigen (PyV mT). In order to carry out the latter studies, we generated and characterized a new mouse model of PyV mT-driven mammary tumourigenesis that incorporates temporal and spatial regulation of PyV mT and Cre recombinase expression. Importantly, mammary tumours lacking p110alpha eventually developed after long latencies in both the ErbB2 and PyV mT strains. We have preliminary evidence to suggest that the emergence of some p110alpha-deficient tumours is associated with an upregulation of osteopontin (OPN), a secreted extracellular matrix-associated protein with relevance in breast cancer. We believe that increased OPN expression could be due to enhanced PI3K signalling through non-alpha p110 isoforms, which in turn may be a result of Pten loss.The results from these studies suggest that activation of the PI3K/Akt pathway might collaborate with HER2/ErbB2 signalling in breast cancer progression and malignancy. Although we can conclude from our work that transformation downstream of activated ErbB2 is initially dependent on the alpha isoform of p110, it is likely that patients with HER2-positive breast cancer will eventually encounter resistance to p110alpha-specific inhibitors used as single agents. In these cases, pan PI3K inhibitors may help in preventing the potential reactivation of PI3K signalling through non-targeted p110 isoforms. La voie de signalisation de la kinase en 3' phosphatidylinositol…