Hyperglycaemia-induced chemoresistance 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 chemoresistance in estrogen receptor (ER alpha) 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 ER alpha positive breast cancer and not for other subtypes. Here we examined the impact of hyperglycaemia on ER alpha negative breast cancer cells and further investigated the mechanism underlying chemoresistance in ER alpha with a view to identifying strategies to alleviate hyperglycaemia-induced chemoresistance. We found that hyperglycaemia-induced chemoresistance was only observed in ER alpha breast cancer cells and was dependent upon the expression of ER alpha as chemoresistance was negated when the ER alpha was silenced. Hyperglycaemia-induced an increase in activation and nuclear localisation of the ER alpha that was downstream of FASN and dependent on the activation of MAPK. We found that fulvestrant successfully negated the hyperglycaemia-induced chemoresistance, whereas tamoxifen had no effect. In summary our data suggests that the ER alpha 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 ER alpha positive breast cancers.