Gery S, Virk R K, Chumakov K, Yu A, Koeffler H P
Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, University of California, Los Angeles, CA 90048, USA.
Oncogene. 2007 Dec 13;26(57):7916-20. doi: 10.1038/sj.onc.1210585. Epub 2007 Jun 18.
Circadian rhythms regulate diverse physiological processes including homeostatic functions of steroid hormones and their receptors. Estrogen receptor-alpha (ERalpha) is essential for normal mammary gland physiology and is a prognostic marker for the treatment of breast cancer. We report that Per2, a core clock gene, links the circadian cycle to the ERalpha signaling network. Binding of enhances ERalpha degradation, while suppression of Per2 levels leads to ERalpha stabilization. In turn, Per2 itself is estrogen inducible in these cells, suggesting a feedback mechanism to attenuate stimulation by estrogen. In addition, overexpression of Per2 in breast cancer cells leads to significant growth inhibition, loss of clonogenic ability and apoptosis. Taken together, these results further support a critical role for peripheral circadian regulation in tissue homeostasis and suggest a novel role for clock genes in estrogen receptor-positive breast cancer.
昼夜节律调节多种生理过程，包括甾体激素及其受体的稳态功能。雌激素受体α（ERα）对于正常乳腺生理功能至关重要，并且是乳腺癌治疗的一个预后标志物。我们报告称，核心生物钟基因Per2将昼夜节律周期与ERα信号网络联系起来。Per2的结合增强了ERα的降解，而Per2水平的抑制则导致ERα稳定。反过来，Per2本身在这些细胞中是雌激素可诱导的，这表明存在一种反馈机制来减弱雌激素的刺激。此外，在乳腺癌细胞中过表达Per2会导致显著的生长抑制、克隆形成能力丧失和细胞凋亡。综上所述，这些结果进一步支持了外周昼夜节律调节在组织稳态中的关键作用，并提示了生物钟基因在雌激素受体阳性乳腺癌中的新作用。
