Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes

Abstract

IntroductionHyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases.MethodsUsing a hyperinsulinemic mouse model (MKR+/+) and the metastatic, c-Myc-transformed mammary carcinoma cell line Mvt1, we investigated how high systemic insulin levels would affect the progression of orthotopically inoculated primary mammary tumors to lung metastases.ResultsWe found that orthotopically injected Mvt1 cells gave rise to larger mammary tumors and to a significantly higher mean number of pulmonary macrometastases in hyperinsulinemic mice over a period of six weeks (hyperinsulinemic, 19.4 ± 2.7 vs. control, 4.0 ± 1.3). When Mvt1-mediated mammary tumors were allowed to develop and metastasize for approximately two weeks and were then surgically removed, hyperinsulinemic mice demonstrated a significantly higher number of lung metastases after a four-week period (hyperinsulinemic, 25.1 ± 4.6 vs. control, 7.4 ± 0.42). Similarly, when Mvt1 cells were injected intravenously, hyperinsulinemic mice demonstrated a significantly higher metastatic burden in the lung than controls after a three-week period (hyperinsulinemic, 6.0 ± 1.63 vs. control, 1.5 ± 0.68). Analysis of Mvt1 cells both in vitro and in vivo revealed a significant up-regulation of the transcription factor c-Myc under hyperinsulinemic conditions, suggesting that hyperinsulinemia may promote c-Myc signaling in breast cancer. Furthermore, insulin-lowering therapy using the beta-adrenergic receptor agonist CL-316243 reduced metastatic burden in hyperinsulinemic mice to control levels.ConclusionsHyperinsulinemia in a mouse model promotes breast cancer metastasis to the lung. Therapies to reduce insulin levels in hyperinsulinemic patients suffering from breast cancer could lessen the likelihood of metastatic progression.

Insulin resistance and cancer: the role of insulin and IGFs

“…However, a recent study involving 25 476 patients with type 2 diabetes has not found any association between HbA1c and risks for all cancers or specific types of cancer (Miao Jonasson et al 2012). Instead, experimental data indicate the overexpression of ILP observed in these patients as a cancer risk factor (Ferguson et al 2012, Gallagher et al 2012. The hyperinsulinemia resulting from the body's attempt to compensate insulin resistance in type 2 diabetes may benefit fully insulin-sensitive cancer tissue by substantially increasing their growth through IR-A/IGF1R increased signaling.…”

“…Such functions are evolutionarily conserved (Duckworth et al 1989, Klusza & Deng 2011, and accordingly, the stimulation of IGF1 axis may represent a common medium for both cancer and diabetes pathogenic processes, together with systemic inflammation and the associated increase in cytokine production (Nunez et al 2006, Dool et al 2011, Faria & Almeida 2012, Ferguson et al 2012, Fernandez-Real & Pickup 2012, Gallagher et al 2012. Except for the IGF2 receptor (IGF2R), following ligand binding, the kinase activity of ILP receptors is activated, leading to the phosphorylation of IR substrates in the cell membrane, which in turn i) activates phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), PI3K/Akt/forkhead box O (FoxO), and Ras/MAPK/extracellular signal-related kinase 1/2 (ERK-1/2) pathways, whose important roles in cancer cell growth and carcinogenesis have been reported (Alvino et al 2011, Tzivion et al 2011; and ii) inactivates glycogen synthase kinase 3b (GSK3b), the inhibitor of the oncogenic b-catenin signaling, through PI3K/Akt signaling pathway, resulting in b-catenin signaling activation that has been associated with cancer stemness and chemoresistance (Fleming et al 2008, Ashihara et al 2009; see Fig.…”

Potential applications for biguanides in oncology

“…Elevated serum levels of insulin or c-peptide (which vary with insulin secretion) are associated with more aggressive behavior and/or increased risk of breast cancer (29,30), colon cancer (31,32), and prostate cancer (33) and with rapid tumor growth in certain model systems (for example, refs. [34][35][36]. Thus, in situations in which metformin leads to substantial reduction in insulin levels, this may inhibit the growth of the subset of tumors that are insulin responsive (2,37,38).…”

High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells

“…Hyperinsulinemia with insulin resistance is a significant risk factor for the development of breast cancer (Papa et al 1997). Ferguson et al (2012) have recently shown that high systemic insulin levels promote breast cancer metastasis in a hyperinsulinemic mouse model by activating c-myc signaling. It has been shown that high-dose human insulin and its analogs promoted T24 (bladder cancer cell), , and PC-3 (prostate cancer cell) proliferation (Weinstein et al 2009, Liu et al 2011b.…”