Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase

L Zeng, Kalina Biernacka, JMP Holly, CE Jarrett, A Morrison, A Morgan, ZE Winters, EJ Foulstone, Julian P Hamilton-Shield, CM Perks

Research output: Contribution to journalArticle (Academic Journal)peer-review

85 Citations (Scopus)

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.
Translated title of the contributionHyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase
Original languageEnglish
Pages (from-to)539 - 551
Number of pages13
JournalEndocrine-Related Cancer
Volume17
Issue number2
DOIs
Publication statusPublished - 1 Jun 2010

Bibliographical note

Publisher: Society of Endocrinology

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