Effective metabolic intervention of breast cancer progression and metastasis.
Authors: Phoenix KN , Vumbaca F , Claffey KP 
Published: December 2010

Abstract
Abstract #6024
Background: Aggressive breast cancers are highly dependent upon glucose for proliferation and survival. Therapeutic modalities that suppress glucose, insulin and IGF-1 have promise as adjuvant therapies to suppress breast cancer progression, metastasis and recurrence. Suppression of glucose availability can trigger the activation of the AMP-dependent kinase (AMPK) in breast cancer cells which may suppress growth. However, AMPK activation can also lead to activation of survival pathways that promote cell survival and expression of VEGF. Previous investigations indicated that estrogen receptor alpha negative tumor cells respond to the AMPK activator, metformin, by repressing proliferation in vitro and conversely inducing tumor growth in vivo (Phoenix et al., Breast Cancer Res Treat, 2008). This study evaluated the efficacy of two metabolic interventions on the 66cl4 murine breast tumor growth and metastasis model.&#x2028; Methods: The 66cl4 murine breast tumor was inoculated into the mammary fat pad of 4-6 week old female Balb/c mice (10 mice/group, 1x106cells/animal). Tumors were allowed to progress to palpable size of 150mm3 volume. Treatment with caloric restriction (70% ab libitum) and metformin at three doses (41, 412 and 825mg/kg/d) were continued for 5 weeks. Tumor volumes were measured twice weekly, blood glucose and animal weight weekly and tumor weight at harvest. Tumors and lungs were analyzed for tumor vascularization, proliferation, apoptosis and cytokine expression and serum evaluated for IGF-1.&#x2028; Results: Caloric restriction significantly suppressed weight gain in Balb/c tumor bearing animals and significantly suppressed glucose compared to ab libitum controls (74.7 +/-2.6 vs. 95.1 +/-2.5, p&lt;0.001). Tumor growth was significantly suppressed over the time course of 6 weeks in the caloric restriction group. Distal metastasis to the lung was also nearly completely inhibited by caloric restriction compared to normal controls. Metabolic intervention with metformin showed a trend of lower serum glucose with increasing doses, however this was not statistically significant. IGF-1 levels at harvest were lower in control mice than those at the highest dose of metformin. Interestingly, high dose metformin resulted in slightly larger tumors and higher tumor weights at harvest. However, histological analysis revealed less viable area and increased apoptosis, although microvascular density and Ki67 proliferation were not affected. High dose metformin reduced distal metastatic lung lesions, consistent with the loss of viable cells in the primary tumors.Conclusions: These results indicate that metabolic interventions may be effective at stabilizing aggressive breast cancers. It is likely that glucose and insulin/IGF-1 can significantly contribute to both primary tumor growth and metastasis. Metformin, the AMPK activator, may be useful in reducing insulin/IGF-1 and glucose in those patients with metabolic syndrome or diabetes which could reduce risk of recurrence where glucose contributes to tumor expansion and survival.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6024.