The role of metformin in obesity-driven endometrial cancer

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Abstract

Endometrial cancer (EC) is the most common gynaecological cancer affecting women in developed countries. Improving outcomes for women who are unfit for primary surgery or have advanced disease remains a challenge. Metformin use is associated with reduced cancer risk in several observational studies of patients with type 2 diabetes. Pre-clinical studies in EC show that metformin reduces cellular proliferation. The work described in this thesis tests the hypothesis that metformin reduces cellular proliferation in vitro and in vivo in type I EC through actions on the PI3K/AKT/mTOR pro-proliferative pathway. First, an in vitro model of EC using cell lines was established to determine the effect of metformin on cellular proliferation. Metformin was found to be cytostatic in a dose-dependent manner; these effects were potentiated in combination with carboplatin and paclitaxel. Metformin was shown to modulate mTOR phosphorylation proteins by immunoblot. Flow cytometric and metabolic assays found metformin to increase mitochondrial mass, but conversely, reduce mitochondrial function. These in vitro findings varied according to glucose concentration and were attenuated in hypoxia. Next, staining and scoring protocols for Ki-67, a marker of cellular proliferation, were established using semi-automated scoring on archived EC tumours. Ki-67 correlated with age, tumour grade and myometrial invasion; high Ki-67 expression was associated with an increased risk of disease recurrence, and was thus a prognostic marker. Finally, a presurgical window study of metformin versus no drug in women with EC demonstrated a 17% reduction in tumour Ki-67 with short-term metformin. Ki-67 response varied positively with increased average daily dose of metformin and negatively with increased BMI. High grade tumours were more hypoxic, according to baseline HIF-1α and the Ki-67 response to metformin was lower in hypoxic tumours. The effect on tumour mTOR phosphorylation events varied, but was not significant after adjusting for changes in controls.In conclusion, these results demonstrated that short-term oral metformin was associated with reduced cellular proliferation in women with EC. The findings from this study require corroboration with a placebo-controlled trial prior to the introduction of metformin as treatment for EC, both as a sole agent and in combination with existing adjuvant therapy. The response to metformin was heterogeneous; tumour hypoxia and metabolic adaptations of cancer cells may lead to metformin-resistance. Future studies should take these modulating effects into account to help identify patients likely to derive clinical benefit from metformin.

Keyword(s)

metformin, endometrial cancer, obesity, diabetes

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