Insulin-induced gene expression changes in breast cancer cells and normal breast epithelial cells.

Obesity increases breast cancer incidence rates in postmenopausal women. Chronic high levels of insulin, present in the majority of obese and insulin resistant patients, may provide the growth promoting stimulus to explain this connection. In this work, the cancer progression and cancer initiating properties of high insulin levels were examined in breast cancer cells (MDA-MB-231) and breast epithelial cells (MCF-10a), respectively. High insulin levels (100 nM) induced differential changes in cell proliferation in the two cell lines used. Human Cancer PathwayFinder DNA Microarrays (SABiosciences) were used to examine gene expression changes after insulin treatment. High insulin levels increased expression of genes involved in cell cycle control (e.g. cyclin D1) and DNA damage repair (e.g. ATM) in MDA-MB 231 cells and in MCF-10a cells (e.g. cyclin E1, CDC25a). Expression of genes responsible for mediating apoptosis and cell senescence (e.g. APAF, BAD, bcl-X) was decreased after insulin treatment in MDA-MB 231 cells but the expression of the same group of genes did not change in MCF-10a cells. High insulin levels increased expression of genes encoding for signal transduction molecules (e.g. AKT1) and transcription factors (e.g. FOS, JUN, MYC), and of genes responsible for invasion and metastasis (e.g. MMP2) in MCF-10a cells whereas gene expression of the same groups of genes did not change or was decreased in MDA-MB 231 cells. These results suggest a role for insulin resistance in breast cancer initiation and progression, aggravating the potential of breast cancer to evade apoptosis, to metastasise and may promote carcinogenesis of healthy epithelial cells.