title: Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase.
abstract: The prognosis for women with breast cancer is adversely affected by the comorbidities of obesity and diabetes mellitus (DM), which are conditions associated with elevated levels of circulating fatty acids, hyperglycaemia and hyperinsulinaemia. We investigated the effects of exposure of non-malignant and malignant human breast epithelial cells to elevated levels of fatty acids and glucose on their growth, survival and response to chemotherapeutic agents. We found that palmitate induced cell death in the non-malignant cells but not in the malignant cells, which was abrogated through the inhibition of ceramide production and by oleate but not by IGF1. Fatty acid synthase (FAS) is responsible for the de novo synthesis of fatty acids from sugars, and is over-expressed in many epithelial cancers. Abundance of FAS was higher in malignant cells than in non-malignant cells, and was up-regulated by IGF1 in both cell types. IGF-induced growth of non-malignant cells was unaffected by suppression of FAS expression, whereas that of malignant cells was blocked as was their resistance to palmitate-induced cell death. Palmitate did not affect cell proliferation, whereas oleate promoted the growth of non-malignant cells but had the opposite effect, that is, inhibition of IGF1-induced growth of malignant cells. However, when the phosphatidylinositol 3-kinase pathway was inhibited, oleate enhanced IGF1-induced growth in both cell types. Hyperglycaemia conferred resistance on malignant cells, but not on non-malignant cells, to chemotherapy-induced cell death. This resistance was overcome by inhibiting FAS or ceramide production. Understanding the mechanisms involved in the associations between obesity, DM and breast cancer may lead to more effective treatment regimens and new therapeutic targets.
authors.affiliation: IGFs and Metabolic Endocrinology Group, Department of Clinical Sciences North Bristol, Learning & Research Building, 2nd floor, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK.
authors.forename: L
authors.initials: L
authors.lastname: Zeng
authors.forename: K M
authors.initials: KM
authors.lastname: Biernacka
authors.forename: J M P
authors.initials: JM
authors.lastname: Holly
authors.forename: C
authors.initials: C
authors.lastname: Jarrett
authors.forename: A A
authors.initials: AA
authors.lastname: Morrison
authors.forename: A
authors.initials: A
authors.lastname: Morgan
authors.forename: Z E
authors.initials: ZE
authors.lastname: Winters
authors.forename: E J
authors.initials: EJ
authors.lastname: Foulstone
authors.forename: J P
authors.initials: JP
authors.lastname: Shield
authors.forename: C M
authors.initials: CM
authors.lastname: Perks
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002518:Ceramides / Q000009:adverse effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019308:Palmitic Acid / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D034741:RNA, Small Interfering; D019308:Palmitic Acid; D064429:Fatty Acid Synthases