生物钟,生化振荡器受环境时间线索调节,包括昼夜周期,在大多数生物过程中具有中心功能。昼夜节律时钟的破坏可以负面地改变乳腺生物学并且可能促进乳腺肿瘤的发展。雌激素受体(ER)的表达状态,孕激素受体(PR),和人表皮生长因子受体2(HER2)用于将乳腺癌分为不同的分子亚型,例如三阴性乳腺癌(TNBC)。先前已经在特定人群中使用相对较小的样本量在乳腺癌中研究了昼夜节律基因的受体状态依赖性表达。这里,使用TCGA-BRCA数据(n=1119),我们发现CRY1,PER1,PER2,PER3,BMAL1,CLOCK,罗拉,RORB,RORC,与ER-状态相比,ER+乳腺癌细胞中的NR1D1、NR1D2和FBXL3更高。同样,我们显示CRY2,PER1,PER2,PER3,BMAL1,RORA,RORB,RORC,NR1D1、NR1D2和FBXL3在PR+乳腺癌细胞中的表达高于PR-乳腺癌细胞。我们报告说,CRY2,PER1,BMAL1和RORA的表达较低,NR1D1的表达较高,在HER2+乳腺癌细胞中与HER2-乳腺癌细胞相比。此外,我们还根据乳腺癌患者的种族和年龄,研究了昼夜节律基因表达的这些受体状态依赖性变化。最后,我们发现非TNBC中CRY2、PER1、PER2、PER3和CLOCK的表达高于TNBC,在亚型中预后最差。我们注意到,我们的发现并不总是与以前在不同种群和生物中进行的较小样本量的研究中报告的观察结果平行。我们的研究表明乳腺癌中的受体状态(因此,乳腺癌的亚型)在其对生物钟基因表达和生物钟破坏的影响方面可能比以前显示的更为重要,ER或PR可能是乳腺癌时间生物学的重要调节因子,在个性化的时间疗法中应该考虑这些因子.
Circadian clocks, biochemical oscillators that are regulated by environmental time cues including the day/night cycle, have a central function in the majority of biological processes. The disruption of the circadian clock can alter breast biology negatively and may promote the development of breast tumors. The expression status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were used to classify breast cancer into different molecular subtypes such as triple-negative breast cancer (TNBC). Receptor status-dependent expression of circadian clock genes have been previously studied in breast cancer using relatively small sample sizes in a particular population. Here, using TCGA-BRCA data (n=1119), we found that the expressions of CRY1, PER1, PER2, PER3, BMAL1, CLOCK, RORA, RORB, RORC, NR1D1, NR1D2, and FBXL3 were higher in ER+ breast cancer cells compared with those of ER- status. Similarly, we showed that transcript levels of CRY2, PER1, PER2, PER3, BMAL1, RORA, RORB, RORC, NR1D1, NR1D2, and FBXL3 were higher in PR+ breast cancer cells than in PR- breast cancer cells. We report that the expressions of CRY2, PER1, BMAL1, and RORA were lower, and the expression of NR1D1 was higher, in HER2+ breast cancer cells compared with HER2- breast cancer cells. Moreover, we studied these receptor status-dependent changes in the expressions of circadian clock genes also based on the race and age of breast cancer patients. Lastly, we found that the expressions of CRY2, PER1, PER2, PER3, and CLOCK were higher in non-TNBC than in TNBC, which has the worst prognosis among subtypes. We note that our findings are not always parallel to the observations reported in previous studies with smaller sample sizes performed in different populations and organisms. Our study suggests that receptor status in breast cancer (thus, subtype of breast cancer) might be more important than previously shown in terms of its influence on the expression of circadian clock genes and on the disruption of the circadian clock, and that ER or PR might be important regulators of breast cancer chronobiology that should be taken into account in personalized chronotherapies.