Garofalo Cecilia, Sisci Diego, Surmacz Eva
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Clin Cancer Res. 2004 Oct 1;10(19):6466-75. doi: 10.1158/1078-0432.CCR-04-0203.
Obesity is a risk factor for breast cancer development in postmenopausal women and correlates with shorter disease-free and overall survival in breast cancer patients, regardless of menopausal status. Adipose tissue is a major source of leptin, a cytokine regulating energy balance and controlling different processes in peripheral tissues, including breast cancer cell growth. Here, we investigated whether leptin can counteract antitumorigenic activities of the antiestrogen ICI 182,780 in breast cancer cells.
Mitogenic response to leptin and the effects of leptin on ICI 182,780-dependent growth inhibition were studied in MCF-7 estrogen receptor alpha-positive breast cancer cells. The expression of leptin receptor and the activation of signaling pathways were studied by Western immunoblotting. The interference of leptin with ICI 182,780-induced estrogen receptor alpha degradation was probed by Western immunoblotting, fluorescence microscopy, and pulse-chase experiments. Leptin effects on estrogen receptor alpha-dependent transcription in the presence and absence of ICI 182,780 were studied by luciferase reporter assays and chromatin immunoprecipitation.
MCF-7 cells were found to express the leptin receptor and respond to leptin with cell growth and activation the signal transducers and activators of transcription 3, extracellular signal-regulated kinase-1/2, and Akt/GSK3/pRb pathways. The exposure of cells to 10 nmol/L ICI 182,780 blocked cell proliferation, induced rapid estrogen receptor alpha degradation, inhibited nuclear estrogen receptor alpha expression, and reduced estrogen receptor alpha-dependent transcription from estrogen response element-containing promoters. All of these effects of ICI 182,780 were significantly attenuated by simultaneous treatment of cells with 100 ng/mL leptin.
Leptin interferes with the effects of ICI 182,780 on estrogen receptor alpha in breast cancer cells. Thus, high leptin levels in obese breast cancer patients might contribute to the development of antiestrogen resistance.
肥胖是绝经后女性患乳腺癌的一个风险因素，且与乳腺癌患者较短的无病生存期和总生存期相关，无论其绝经状态如何。脂肪组织是瘦素的主要来源，瘦素是一种调节能量平衡并控制包括乳腺癌细胞生长在内的外周组织中不同过程的细胞因子。在此，我们研究了瘦素是否能抵消抗雌激素ICI 182,780在乳腺癌细胞中的抗肿瘤活性。
在MCF-7雌激素受体α阳性乳腺癌细胞中研究了对瘦素的促有丝分裂反应以及瘦素对ICI 182,780依赖性生长抑制的影响。通过Western免疫印迹法研究了瘦素受体的表达和信号通路的激活。通过Western免疫印迹法、荧光显微镜检查和脉冲追踪实验探究了瘦素对ICI 182,780诱导的雌激素受体α降解的干扰作用。通过荧光素酶报告基因检测和染色质免疫沉淀法研究了在有或无ICI 182,780存在的情况下瘦素对雌激素受体α依赖性转录的影响。
发现MCF-7细胞表达瘦素受体，并通过细胞生长以及激活转录信号转导子和激活子3、细胞外信号调节激酶-1/2和Akt/GSK3/pRb通路对瘦素有反应。将细胞暴露于10 nmol/L的ICI 182,780会阻断细胞增殖、诱导雌激素受体α快速降解、抑制核雌激素受体α表达，并降低含雌激素反应元件启动子的雌激素受体α依赖性转录。通过用100 ng/mL瘦素同时处理细胞，ICI 182,780的所有这些作用均被显著减弱。
瘦素干扰了ICI 182,780对乳腺癌细胞中雌激素受体α的作用。因此，肥胖乳腺癌患者体内的高瘦素水平可能导致抗雌激素耐药性的产生。
