Abstract
We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.
Highlights
The American Cancer Society estimates that nearly 50,000 new cases of endometrial carcinoma will be diagnosed in 2014 [1]
In a preoperative window study in obese, nondiabetic endometrial cancer patients, we demonstrate that metformin significantly decreased proliferation in the malignant endometrium, with parallel effects on inhibition of the mammalian target of rapamycin (mTOR) pathway
Differential effects of metformin were found in the serum of patients whose endometrial tumors responded favorably to drug exposure when compared to those who did not respond, as demonstrated by metabolomic profiling
Summary
The American Cancer Society estimates that nearly 50,000 new cases of endometrial carcinoma will be diagnosed in 2014 [1]. Diabetes, and insulin resistance are well-known risk factors that drive the development of endometrial cancer [2, 3]. Obesity is a risk factor for endometrial cancer, and may be associated with an increased risk of death from this disease [4]. An association with all-cause mortality in endometrial cancer as a function of body mass has been found, with obese patients having a relative risk of death 2.5 times higher than their nonobese counterparts and morbid obesity carrying a relative risk of over six times that of patients with a normal body mass index (BMI) [5]. The severity of obesity-associated endometrial cancer suggests that tumors arising in the obese state may display altered tumor biology (or changes in the microenvironment) that drive carcinogenesis, providing a unique opportunity to inhibit obesity-activated pathways as a therapeutic strategy
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