Hyperglycaemia-induced chemo-resistance in breast cancer cells: role of the estrogen receptor

Breast cancer patients with diabetes respond less well to chemotherapy; in keeping with this we determined previously that hyperglycaemia induced chemo-resistance in estrogen receptor (ERα) positive breast cancer cells and showed that this was mediated by fatty acid synthase (FASN). More recent evidence suggests that the effect of metabolic syndrome and diabetes is not the same for all subtypes of breast cancer with inferior disease-free survival and worse overall survival only found in women with ERα positive breast cancer and not for other subtypes. Here we examined the impact of hyperglycaemia on ERα negative breast cancer cells and further investigated the mechanism underlying chemo-resistance in ERα with a view to identifying strategies to alleviate hyperglycaemia-induced chemo-resistance. We found that hyperglycaemia-induced chemo-resistance was only observed in ERα breast cancer cells and was dependent upon the expression of ERα as chemo-resistance was negated when the ERα was silenced. Hyperglycaemia induced an increase in activation and nuclear localisation of the ERα that was downstream of FASN and dependent on the activation of mitogen activated protein kinase (MAPK). We found that Fulvestrant successfully negated the hyperglycaemia-induced chemo-resistance, whereas Tamoxifen had no effect. In summary our data suggests that the ERα may be a predictive marker of poor response to chemotherapy in breast cancer patients with diabetes. It further indicates that anti-estrogens could be an effective adjuvant to chemotherapy in such patients and indicates the importance for the personalised management of breast cancer patients with diabetes highlighting the need for clinical trials of tailored chemotherapy for diabetic patients diagnosed with ERα positive breast cancers.