title: Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor.
abstract: Breast cancer patients with diabetes respond less well to chemotherapy; in keeping with this we determined previously that hyperglycaemia-induced chemoresistance 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 chemoresistance in ERα with a view to identifying strategies to alleviate hyperglycaemia-induced chemoresistance. We found that hyperglycaemia-induced chemoresistance was only observed in ERα breast cancer cells and was dependent upon the expression of ERα as chemoresistance 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 MAPK. We found that fulvestrant successfully negated the hyperglycaemia-induced chemoresistance, 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.
authors.affiliation: IGFs and Metabolic Endocrinology GroupSchool of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UKDepartment of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK.
authors.forename: L
authors.initials: L
authors.lastname: Zeng
authors.affiliation: IGFs and Metabolic Endocrinology GroupSchool of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UKDepartment of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK.
authors.forename: H A
authors.initials: HA
authors.lastname: Zielinska
authors.affiliation: IGFs and Metabolic Endocrinology GroupSchool of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UKDepartment of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK.
authors.forename: A
authors.initials: A
authors.lastname: Arshad
authors.affiliation: IGFs and Metabolic Endocrinology GroupSchool of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UKDepartment of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Shield
authors.affiliation: IGFs and Metabolic Endocrinology GroupSchool of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UKDepartment of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK.
authors.forename: A
authors.initials: A
authors.lastname: Bahl
authors.affiliation: IGFs and Metabolic Endocrinology GroupSchool of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UKDepartment of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK.
authors.forename: J M P
authors.initials: JM
authors.lastname: Holly
authors.affiliation: IGFs and Metabolic Endocrinology GroupSchool of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UKDepartment of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK claire.m.perks@bristol.ac.uk.
authors.forename: C M
authors.initials: CM
authors.lastname: Perks
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology
chemical_list: D002518:Ceramides; D047628:Estrogen Receptor alpha; D004317:Doxorubicin; D017239:Paclitaxel
keywords: breast cancer; chemoresistance; estrogen receptor; hyperglycaemia