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.
Highlights
Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has been identified as a specific factor which can worsen breast cancer prognosis
A significant increase in Mvt1-mediated mammary tumor growth was observed in (MCK) muscle creatinine kinase (MKR)+/+ mice compared to controls (Figure 1A), which was confirmed by the terminal weights of tumors (Figure 1B)
Mammary tumors express elevated levels of c-Myc, MMP9, insulin receptor (IR), insulin-like growth factor receptor (IGF-IR) and vascular endothelial growth factor (VEGF) In order to examine the effects of hyperinsulinemia on the metastasis of tumor cells from the primary site, we examined levels of c-Myc, matrix metalloprotease (MMP)-9, IR, IGF-IR and VEGF in tumor tissue extracted from control and MKR +/+ mice
Summary
Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has been identified as a specific factor which can worsen breast cancer prognosis. A high rate of mortality persists due to the emergence of pulmonary metastases. Epidemiological studies have recently demonstrated that the risks for breast cancer incidence and mortality are increased in individuals suffering from T2D [3,4,5,6]. A positive correlation has recently been reported with breast cancer incidence [7,8]. In vitro, numerous studies have reported that breast cancer cell lines proliferate in response to insulin [13,14,15]
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