Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Cell Cycle. 2012 Jan 15;11(2):350-60. doi: 10.4161/cc.11.2.18792.
Most physiological and biological processes are regulated by endogenous circadian rhythms under the control of both a master clock, which acts systemically and individual cellular clocks, which act at the single cell level. The cellular clock is based on a network of core clock genes, which drive the circadian expression of non-clock genes involved in many cellular processes. Circadian deregulation of gene expression has emerged to be as important as deregulation of estrogen signaling in breast tumorigenesis. Whether there is a mutual deregulation of circadian and hormone signaling is the question that we address in this study. Here we show that, upon entrainment by serum shock, cultured human mammary epithelial cells maintain an inner circadian oscillator, with key clock genes oscillating in a circadian fashion. In the same cells, the expression of the estrogen receptor α (ER A) gene also oscillates in a circadian fashion. In contrast, ER A-positive and -negative breast cancer epithelial cells show disruption of the inner clock. Further, ER A-positive breast cancer cells do not display circadian oscillation of ER A expression. Our findings suggest that estrogen signaling could be affected not only in ER A-negative breast cancer, but also in ER A-positive breast cancer due to lack of circadian availability of ER A. Entrainment of the inner clock of breast epithelial cells, by taking into consideration the biological time component, provides a novel tool to test mechanistically whether defective circadian mechanisms can affect hormone signaling relevant to breast cancer.
大多数生理和生物过程都受到内源性昼夜节律的调节，这种节律受到主钟的控制，主钟在系统中起作用，而个体细胞钟则在单细胞水平上起作用。细胞钟基于核心时钟基因网络，驱动涉及许多细胞过程的非时钟基因的昼夜表达。基因表达的昼夜失调已经变得与乳腺癌发生中的雌激素信号失调一样重要。昼夜节律和激素信号是否存在相互失调，是我们在本研究中要解决的问题。在这里，我们表明，在血清休克的驯化下，培养的人乳腺上皮细胞维持内在的生物钟振荡器，关键的时钟基因以昼夜节律的方式振荡。在相同的细胞中，雌激素受体 α (ER A)基因的表达也以昼夜节律的方式振荡。相比之下，ER A阳性和 ER A阴性乳腺癌上皮细胞显示出内在时钟的破坏。此外，ER A阳性乳腺癌细胞不显示 ER A表达的昼夜振荡。我们的发现表明，由于 ER A 的昼夜可用性缺失，雌激素信号不仅在 ER A阴性乳腺癌中受到影响，而且在 ER A阳性乳腺癌中也受到影响。考虑到生物时间成分，对乳腺上皮细胞内在时钟的驯化提供了一种新的工具，可以从机制上测试有缺陷的昼夜机制是否会影响与乳腺癌相关的激素信号。
