Molecular aspects of insulin resistance, cell signaling pathways and breast cancer in relation to obesity.

Weichhaus, M.; Broom, J.; Wahle, K.; Bermano, G.

Abstract

A growing number of clinical studies validate a relation of insulin resistance and breast cancer in obese patients. We hypothesised that high plasma insulin levels cause aberrant insulin signalling in breast epithelial cells which may be responsible for an increase in cell proliferation, indicative of potential carcinogenesis and increased cancer progression. It was of particular interest to determine any differences of high insulin concentrations in activating the phosphoinositide-3 kinase (PI-3 kinase) pathway or the mitogen-activated protein kinase (MAP kinase) pathway, the latter being linked to increased cell proliferation. We used two cell line models to investigate the carcinogenic (MCF-10A, immortalised breast epithelial cells) and cancer progression (MDA-MB-231, ER-negative breast cancer cells) potential of insulin. Insulin treatment (100 nM, 24 h) increased cell proliferation in MCF-10A cells, but had no cell proliferative effect on MDA-MB-231 cells. Additionally expression of PCNA as marker of proliferation was tested. The use of PI-3 kinase and MAP kinase specific inhibitors (Wortmannin and PD98059, respectively) demonstrated both pathways being responsible for the observed increase in cell proliferation (MCF-10A). Simultaneous treatment with both inhibitors eliminated insulin induced cell proliferation entirely. Phosphorylation of ERK1/2 was examined as specific activity measurement of MAP kinase pathway. Insulin induced higher phosphorylation levels in MCF-10A cells than in MDA-MB-231. These preliminary results suggest that insulin may initiate carcinogenesis of breast epithelial cells by increasing cell proliferation rather than increasing cancer progression of existing tumours. These effects may be mediated by insulin activating both the PI-3 kinase and the MAP kinase signalling pathways.

Citation

WEICHHAUS, M., BROOM, J., WAHLE, K. and BERMANO, G. 2008. Molecular aspects of insulin resistance, cell signaling pathways and breast cancer in relation to obesity. Presented at 16th European congress on obesity 2008 (ECO 2008), 14-17 May 2008, Geneva, Switzerland.

• Presentation Conference Type: Poster
• Conference Name: 16th European congress on obesity 2008 (ECO 2008)
• Start Date: May 14, 2008
• End Date: May 17, 2008
• Deposit Date: Jul 8, 2021
• Publicly Available Date: Jul 8, 2021
• Peer Reviewed: Peer Reviewed
• Keywords: Insulin resistance; Breast cancer; Obesity; Increase in cell proliferation; Cancer progression
• Public URL: https://rgu-repository.worktribe.com/output/1380312
• Related Public URLs: http://hdl.handle.net/10059/591; https://rgu-repository.worktribe.com/output/1148634; https://rgu-repository.worktribe.com/output/1380321; https://rgu-repository.worktribe.com/output/1380292