title: A novel role for insulin resistance in the connection between obesity             and postmenopausal breast cancer.
abstract: The past two decades have seen a drastic increase in obesity rates in Western             societies and emerging countries. As such, it has become increasingly important             to understand the molecular mechanisms by which obesity affects the risk of developing             associated co-morbidities. The present study aimed at identifying the effect of             insulin on breast cancer and breast epithelial cells, reflective of obesity-associated             hyperinsulinaemia, as a molecular explanation for the increased risk of oestrogen             receptor-negative postmenopausal breast cancer in obese women. Both of the examined             breast cancer cell lines (MDA‑MB-231 and SK-BR-3) showed intact insulin signalling             (insulin receptor phosphorylation and activation of phosphoinositol-3 kinase and             mitogen-activated protein kinase cell signalling pathways), with MDA-MB-231 cells             showing aberrantly amplified insulin signalling. Insulin did not induce a physiologically             significant change in proliferation or apoptosis in either cell line. MDA-MB-231             cells showed decreased cell proliferation and increased S-phase population, while             SK-BR-3 cells showed increased cyclin D and cyclin E gene expression and increased             necrosis after insulin treatment. Hyperinsulinaemia may not be a universal mechanism             by which obesity affects breast cancer progression. Normal breast epithelial cells             (MCF-10A) showed intact insulin signalling, increased cell proliferation and reduced             apoptosis after insulin treatment, suggesting cell growth and survival-promoting             effects of insulin on these cells. Thus, hyperinsulinaemia may affect breast cancer             aetiology rather than progression and this finding may provide a novel molecular             mechanism for the role of insulin in the promotion of increased postmenopausal             breast cancer risk in obese women.
authors.affiliation: Centre for Obesity Research and Epidemiology, Robert Gordon University, Aberdeen, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Weichhaus
authors.forename: John
authors.initials: J
authors.lastname: Broom
authors.forename: Klaus
authors.initials: K
authors.lastname: Wahle
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bermano
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056741:Cyclin D / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010766:Phosphorylation; D017698:Postmenopause; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D007328:Insulin; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases