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.
Endocr Relat Cancer. 2010 May 18;17(2):539-51. doi: 10.1677/ERC-09-0221. Print 2010 Jun.
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.
肥胖症和糖尿病（DM）合并症会对乳腺癌女性的预后产生不利影响，这些病症与循环脂肪酸、高血糖和高胰岛素血症水平升高有关。我们研究了将非恶性和恶性人乳腺上皮细胞暴露于高水平脂肪酸和葡萄糖对其生长、存活和对化疗药物反应的影响。我们发现，棕榈酸可诱导非恶性细胞死亡，但不诱导恶性细胞死亡，通过抑制神经酰胺的产生和油酸但不通过 IGF1 可阻断这种作用。脂肪酸合酶（FAS）负责从糖从头合成脂肪酸，在许多上皮癌中过度表达。恶性细胞中 FAS 的丰度高于非恶性细胞，并且在两种细胞类型中 IGF1 都可上调其表达。IGF 诱导非恶性细胞生长不受 FAS 表达抑制的影响，而恶性细胞的生长受到抑制，并且对棕榈酸诱导的细胞死亡具有抗性。棕榈酸不影响细胞增殖，而油酸促进非恶性细胞的生长，但对恶性细胞则产生相反的效果，即抑制 IGF1 诱导的生长。然而，当抑制磷酸肌醇 3-激酶途径时，油酸增强了两种细胞类型中 IGF1 诱导的生长。高血糖使恶性细胞对化疗诱导的细胞死亡产生抗性，但对非恶性细胞没有抗性。通过抑制 FAS 或神经酰胺的产生可克服这种抗性。了解肥胖症、DM 和乳腺癌之间关联所涉及的机制可能会导致更有效的治疗方案和新的治疗靶点。
