Insulin and insulin-like growth factors (IGFs) are well known as key regulators of energy metabolism and growth. There is now considerable evidence that these hormones and the signal transduction networks they regulate have important roles in neoplasia. Epidermiological, clinical and laboratory research methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Pharmacological strategies under study include the use of novel receptor-specific antibodies, receptor kinase inhibitors and AMP-activated protein kinase activators such as metformin. There is evidence that insulin and IGF signalling may also be relevant to dietary and lifestyle factors that influence cancer risk and cancer prognosis. Recent results are encouraging and have justified the expansion of many translational research programmes.

Insulin and insulin-like growth factor signalling in neoplasia

https://www.cell.com/cell/pdf/0092-8674(87)90193-0.pdf

Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells

Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K-AKT pathway inhibitors.

/pdf/the-insulin-and-insulin-like-growth-factor-receptor-family-4t4g3oba1l.pdf

The insulin and insulin-like growth factor receptor family in neoplasia: an update

The increasing incidence of obesity and its co-morbid conditions poses a great challenge to global health. In addition to cardiovascular disease and diabetes, epidemiological data demonstrate a link between obesity and multiple types of cancer. The molecular mechanisms underlying how obesity causes an increased risk of cancer are poorly understood. Obesity disrupts the dynamic role of the adipocyte in energy homeostasis, resulting in inflammation and alteration of adipokine (for example, leptin and adiponectin) signalling. Additionally, obesity causes secondary changes that are related to insulin signalling and lipid deregulation that may also foster cancer development. Understanding these molecular links may provide an avenue for preventive and therapeutic strategies to reduce cancer risk and mortality in an increasingly obese population.

Molecular mechanisms of cancer development in obesity

The anti-diabetic drug metformin reduces human cancer incidence and improves the survival of cancer patients, including those with breast cancer. We studied the activity of metformin against diverse molecular subtypes of breast cancer cell lines in vitro.  Metformin showed biological activity against all estrogen receptor (ER) positive and negative, erbB2 normal and abnormal breast cancer cell lines tested. It inhibited cellular proliferation, reduced colony formation and caused partial cell cycle arrest at the G1 checkpoint. Metformin did not induce apoptosis (as measured by DNA fragmentation and PARP cleavage) in luminal A, B or erbB2 subtype breast cancer cell lines. At the molecular level, metformin treatment was associated with a reduction of cyclin D1 and E2F1 expression with no changes in p27kip1 or p21waf1. It inhibited mitogen activated protein kinase (MAPK) and Akt activity, as well as the mammalian target of rapamycin (mTOR) in both ER positive and negative, erbB2-overexpressing and erbB2-norma...

Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro

The mechanisms of steroid and peptide hormone action in human breast cancer are poorly understood. We have previously characterized a cell line of human breast cancer in long-term tissue culture that possesses various steroid hormone receptors and responses, providing a model for the study of steroid hormone action. The present studies describe a human breast cancer in vitro that responds to physiologie concentrations of insulin with an increased rate of macromolecular synthesis and growth. Thymidine and uridine incorporation in cells in serum-free medium are stimulated by 10(-11) M insulin and are maximal with 10(-8) M. Leucine incorporation is stimulated by 5 X 10(-11) M insulin and is maximal with 10(-9) M. Significant stimulation of uridine and leucine incorporation is evident by 3 hr and maximal by 10 hr. A 10-hr lag period exists for insulin stimulation of thymidine incorporation, which is maximal form 14 to 24 hr. The effect of 10(-8) M insulin on macromolecular synthesis is accompanied by a 69% increase above controls in the number of cells after 24 hr. The effect on macromolecular synthesis is observed in glucose-free medium. Insulin's effect on protein synthesis is not blocked by inhibition of RNA synthesis with actinomycin D. Glucocorticoids partially inhibit the action of insulin in these cells. This system provides a model for studying insulin action, and suggests that some human breast cancer may show growth regulation by insulin.

https://www.pnas.org/content/pnas/73/12/4536.full.pdf

Hormone responsive human breast cancer in long-term tissue culture: effect of insulin.

Insulin interaction with four human breast cancer cell lines in tissue culture was studied with respect to specific binding to receptors, degradation, and biological responsiveness. All four lines bound and degraded 125I-labeled insulin. Binding and degradation were time, temperature, and pH dependent. Unlabeled insulin competed with 125I-labeled insulin for binding to the breast cells with half-maximal inhibition of binding being observed with less than 0.6 ng/ml for three of the four lines. Other peptides competed for insulin binding in proportion to their biological potency. Scatchard analysis of the insulin binding data revealed curvilinear plots consistent with negative cooperativity, and this was confirmed by kinetic studies of dissociation. Quantitative analysis of insulin degradation revealed a similar Km for all four cell lines (1.0 to 2.2 × 10-7m), whereas maximal velocities varied over a 7-fold range. Bacitracin, a polypeptide antibiotic, inhibited insulin degradation by all four lines. In one cell line, typical competitive binding data and Scatchard plots were obtained only after inhibition of degradation with bacitracin. Insulin stimulated precursor incorporation into macromolecules and fatty acids in only two of the four cell lines; with these, significant stimulation was seen with concentrations as low as 0.6 ng/ml. No correlation was found between the amount of specific binding, receptor concentration, or receptor affinity and the ability of insulin to stimulate the cells, suggesting a defect distal to the hormone-receptor interaction in the two unresponsive lines. The two responsive cell lines showed the most insulin degradation. These human cell lines should provide a useful tool for further study of the complex mechanisms of insulin action and for the study of factors that regulate growth of human breast cancer.

https://cancerres.aacrjournals.org/content/canres/38/1/94.full.pdf

Correlation Among Insulin Binding, Degradation, and Biological Activity in Human Breast Cancer Cells in Long-Term Tissue Culture

We have examined the interaction of dexamethasone with the ZR75-1 human breast cancer cell line to determine if glucocorticoids might directly inhibit growth of breast cancer cells. Growth of these cells in serum-free medium was stimulated significantly by physiological concentrations of insulin (0.1 to 1.0 nm). Pharmacological concentrations of dexamethasone (10 nm) reduced cell number below that found in controls and nearly abolished the effect of insulin after several days in culture. Thymidine and uridine, but not leucine, incorporation into macromolecules or acetate incorporation into fatty acids were similarly inhibited by dexamethasone in the presence or absence of insulin. Dexamethasone did not inhibit insulin effects by altering insulin receptor affinity or concentration, as determined by Scatchard analyses of insulin binding. Net thymidine uptake into the trichloroacetic acid-soluble fraction of the cell was stimulated by insulin and inhibited by dexamethasone. Dexamethasone also inhibited thymidine kinase activity in both control and insulin-stimulated cells. These data suggest multiple potential sites of glucocorticoid action that directly oppose the effects of insulin. They also suggest that glucocorticoids have a direct inhibitory effect on proliferation of human breast cancer cells, which may help explain breast tumor regression following pharmacological glucocorticoid therapy.

https://cancerres.aacrjournals.org/content/canres/39/7_Part_1/2422.full.pdf

Direct Inhibition of Growth and Antagonism of Insulin Action by Glucocorticoids in Human Breast Cancer Cells in Culture

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C. K. Osborne

Papers

Hormone responsive human breast cancer in long-term tissue culture: effect of insulin.

Correlation Among Insulin Binding, Degradation, and Biological Activity in Human Breast Cancer Cells in Long-Term Tissue Culture

Direct Inhibition of Growth and Antagonism of Insulin Action by Glucocorticoids in Human Breast Cancer Cells in Culture

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Insulin receptors in human breast cancer: relationship of binding, degradation and biological activity