Uncoupling effects of ERalfa on LKB1/AMPK interaction upon adiponectin exposure in breast cancer

Adipose tissue is a metabolic and endocrine organ that secretes numerous bioactive molecules called adipocytokines. Among these, adiponectin has been argued to have a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMP-activated protein kinase (AMPK), mainly activated by Liver Kinase B1 (LKB1). Here, we demonstrated how the ERalfa/LKB1 interaction may negatively interfere with the capability of LKB1 to phosphorylate AMPK and then inhibit its downstream signaling TSC2/mTOR/p70S6k. In MCF-7 cells upon adiponectin AMPK signaling was not working, keeping its downstream protein Acetyl-CoA Carboxylase (ACC) still active. In contrast, in MDA-MB-231 cells the phosphorylation of AMPK and ACC was enhanced with consequent inhibition of both lipogenesis and cell growth. Thus, upon adiponectin, ERalfa signaling switched the energy balance of breast cancer cells towards a lipogenic phenotype. In other words, adiponectin in all the concentrations tested played an inhibitory role on ERalpha-negative breast cancer cell growth and progression either in vitro or in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, worked on ERalfa-positive cells as a growth factor, stimulating their growth and progression. The latter effect seems to be blunted in vivo only in the presence of high adiponectin concentration. Based on the present results, it can be concluded that if we prospectively address adiponectin as a pharmacological tool, a separate therapeutic treatment should be carefully assessed in ERalfa-positive and negative breast-cancer patients.

脂肪组织是兼具代谢与内分泌功能的器官，可分泌多种被称为脂肪细胞因子的生物活性分子。其中，脂联素被认为在肥胖相关乳腺癌中发挥关键调控作用。脂联素信号通路的核心效应分子为腺苷酸活化蛋白激酶（AMP-activated protein kinase），其激活主要依赖于肝激酶B1（Liver Kinase B1）。本研究阐明了雌激素受体α与LKB1的相互作用如何负向调控LKB1对AMPK的磷酸化能力，进而抑制其下游信号通路TSC2/mTOR/p70S6k。在经脂联素处理的MCF-7细胞中，AMPK信号通路无法正常激活，其下游靶蛋白乙酰辅酶A羧化酶（Acetyl-CoA Carboxylase）仍维持活性状态。与之相反，在MDA-MB-231细胞中，AMPK与ACC的磷酸化水平显著升高，同时脂肪生成与细胞增殖均受到抑制。综上，脂联素可通过雌激素受体α信号通路重塑乳腺癌细胞的能量平衡，使其偏向脂肪生成表型。换言之，在所测试的所有浓度下，脂联素在体外与体内实验中均能抑制雌激素受体α阴性乳腺癌细胞的生长与进展。而低浓度脂联素（与肥胖患者循环中的脂联素水平相当）则可作用于雌激素受体α阳性细胞，发挥生长因子的作用，促进其增殖与进展；这一促增殖效应仅在高浓度脂联素存在的体内环境中被阻断。基于本研究结果，可得出如下结论：若将脂联素作为药理学干预手段，需针对雌激素受体α阳性与阴性乳腺癌患者分别评估其治疗方案的安全性与有效性。