Igf2 ligand dependency of Pten(+/-) developmental and tumour phenotypes in the mouse.

The tumour suppressor PTEN is a key negative regulator of the PI3K-Akt pathway, and is frequently either reduced or lost in human tumours. Murine genetic studies have confirmed that reduction of Pten promotes tumourigenesis in multiple organs, and demonstrated dependency of tumour development on the activation of downstream components such as Akt. Insulin-like growth factors (IGFs) act via IGF1R to activate the PI3K-Akt pathway, and are commonly upregulated in cancer. A context-dependent interplay between IGFs and PTEN exists in normal tissue and tumours; increased IGF2 ligand supply induces Pten expression creating an autoregulatory negative feedback loop, whereas complete loss of PTEN may either cooperate with IGF overexpression in tumour promotion, or result in desensitisation to IGF ligand. However, it remains unknown whether neoplasia associated with Pten loss is dependent on upstream IGF ligand supply in vivo. We evaluated this by generation of Pten(+/-) mice with differing allelic dosage of Igf2, an imprinted gene encoding the potent embryonic and tumour growth factor Igf2. We show that biallelic Igf2 supply potentiates a previously unreported Pten(+/-) placental phenotype and results in strain-dependent cardiac hyperplasia and neonatal lethality. Importantly, we also show that the effects of Pten loss in vivo are modified by Igf2 supply, as lack of Igf2 results in extended survival and delayed tumour development while biallelic supply is associated with reduced lifespan and accelerated neoplasia in females. Furthermore, we demonstrate that reduction of PTEN protein to heterozygote levels in human MCF7 cells is associated with increased proliferation in response to IGF2, and does not result in desensitisation to IGF2 signalling. These data indicate that the effects of Pten loss at heterozygote levels commonly observed in human tumours are modified by Igf2 ligand, and emphasise the importance of the evaluation of upstream pathways in tumours with Pten loss

Preclinical vaccines against mammary carcinoma.

Vaccines against human breast cancer are an unfulfilled promise. Despite decades of promising preclinical and clinical research, no vaccine is currently available for breast cancer patients. Preclinical research has much to do with this failure, as early mouse models of mammary carcinoma did not mirror the molecular, cellular, antigenic and immunological features of human breast cancer. The advent of HER-2 transgenic mice gave impulse to a new generation of cell and DNA vaccines against mammary carcinoma, that in turn led to the definition of significant antigenic (oncoantigens) and cellular (cancer-initiating cells, preneoplastic lesions, incipient metastases) targets. Future preclinical developments will include the discovery of novel oncoantigens in HER-2-negative mammary carcinoma and the targeting of activated HER-2 molecular variants. Translation to clinically effective vaccines will be fostered not only by new preclinical model systems, but also by the possibility to conduct veterinary vaccination trials in companion animals