Anschutz Health and Wellness Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
Cancer Res. 2012 Dec 15;72(24):6490-501. doi: 10.1158/0008-5472.CAN-12-1653. Epub 2012 Dec 7.
Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight gain may provide a life cycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake, and proliferation markers. Treatment with the antidiabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast cancer.
肥胖绝经后妇女患乳腺癌的风险增加，临床结局比瘦绝经后妇女差。然而，这些关联的机制尚不清楚。最近的啮齿动物模型研究发现，乳腺癌促进存在一个脆弱期，即在卵巢功能丧失（手术卵巢切除术；OVX）后体重增加时出现。因此，短暂的体重增加期可能为绝经后乳腺癌的预防或治疗提供一个特定于生命周期的机会。我们假设，肥胖动物在 OVX 之前代谢调节受损加上 OVX 诱导的正能量失衡，可能共同促进肿瘤生长和进展。为了确定肥胖和瘦啮齿动物在 OVX 诱导的体重增加的代谢反应是否存在差异，以及这种差异是否会影响后期乳腺肿瘤的代谢，我们在绝经脆弱期进行了营养示踪研究。瘦动物优先将多余的营养物质沉积到乳腺和外周组织中，而不是沉积到相邻的肿瘤中。相反，肥胖动物将多余的营养物质沉积到肿瘤本身。值得注意的是，肥胖动物的肿瘤还表现出孕激素受体（PR）的表达增加。PR 表达的升高与肿瘤中糖酵解和脂肪生成酶、葡萄糖摄取和增殖标志物的表达呈正相关。在卵巢切除术后体重增加期间用抗糖尿病药物二甲双胍治疗会导致肿瘤消退和肿瘤中 PR 表达下调。临床分析绝经后妇女的乳腺肿瘤表达谱分析表明，PR 表达与类似的代谢上调模式相关，支持 PR+肿瘤在绝经后具有增强的代谢能力的观点。我们的发现具有解释性，有助于理解为什么肥胖的绝经后妇女患乳腺癌的风险增加。
