| | Category | ME | L26 | The Synergistic Effect of the PIK3CA gene mutation H1047R and the |
| | Her 2 gene i |
| | Abstract | The PI3K signaling pathway is directly responsible for cell proliferation, |
| | survival, and the many processes which contribute to the growth of |
| | breast cancer. Phosphatidylinositol 3- kinases (PI3Ks) are a group of lipid |
| | kinases that are major players in this pathway. Class I PI3Ks are |
| | composed of two subunits, an 85 kDA adaptor subunit (p85) that lacks |
| | PI3K activity, and a 110 kDA catalytic subunit (p110), which is coded by |
| | the PIK3CA gene. PIK3CA has been found to have a 20-30% somatic |
| | mutation rate in breast cancer. In recent studies, H1047R, a mutation |
| | position of PIK3CA, was found to have the fastest and strongest growing |
| | ability with or without the epidermal growth factor (EGF), and was the |
| | most potent mutation. Her2 (c-erbB-2 / Neu), or the Human epidermal |
| | growth factor 2, is a proto-oncogene that is over-expressed in 30% of |
| | breast cancer, making Her 2 amplification the most frequent mutation in |
| | breast cancer. Her 2 codes for a tyrosine-kinase growth factor receptor, |
| | which regulates normal cell function, growth, and proliferation. In clinical |
| | studies it has been shown that the PIK3CA gene is connected with Her 2, |
| | maybe because the tyrosine kinase growth factor receptors that Her2 |
| | code for phosphorylate and activate the PI3K pathway. Furthermore in |
| | clinical studies patients with no PIK3CA mutations had less resistance to |
| | Her2 treatment than patients with any kind of PIK3CA mutation, indicating a |
| | possible relationship between the two genes and also between the two |
| | genes for treatment. |
| | In this study, a cell proliferation, colony formation, and invasion assay |
| | were performed using the MCF10A cell line with over-expressed H1047R |
| | gene mutation, Her 2, both genes, or Lac Z as a control, to determine if the |
| | two genes have a synergistic effect. Furthermore, the MCF10A cell line |
| | with both over-expressed Her2 and H1047R were tested for cell growth in |
| | the presence of different concentrations and combinations of the Her2 |
| | and PIK3CA inhibitors in order to see a possible benefit of having both |
| | genes present during treatment with inhibitors. |
| | In conclusion, it was found that the PIK3CA mutation H1047R and the |
| | Her2 gene have a synergistic effect in the growth of breast cancer, since |
| | in both the cell proliferation and colony formation assay the added effect |
| | of both genes increased cell growth and colony formation numbers. Also, |
| | when inhibitors were added to the cells with both Her2 and H1047R |
| | mutations, it was proven that when the PIK3CA inhibitor LY294002 was |
| | used when the Her2 inhibitor, CP-724714, was also added, cell growth |
| | and colony formation was low also supporting their synergistic effect. |
| | Overall, these results suggest that the mutation H1047R in the PIK3CA |
| | gene and the Her2 gene are synergistic and that as a result these genes |
| | may be a potent target for anti-cancer therapies in breast cancer. |
| | Bibliography | . Jitesh P. Jani, Richard S. Finn, Mary Campbell, et al. Discovery and |
| | Pharmacologic Characterization of |
| | CP-724,714, a Selective ErbB2 Tyrosine Kinase Inhibitor Cancer Res |
| | 2007;67:9887-9893. |