Dataset Information

Loss of circadian clock gene expression is associated with tumor progression in breast cancer.

ABSTRACT: Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., CLOCK, PER1, PER2, PER3, CRY2, NPAS2 and RORC) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted P < 0.05). Stratification according to molecular subtype revealed prognostic relevance for PER1, PER3, CRY2 and NFIL3 in the ER+/HER2- subgroup, CLOCK and NPAS2 in the ER-/HER2- subtype, and ARNTL2 in HER2+ breast cancer. In the multivariate Cox model, only PER3 (HR = 0.66; P = 0.016) and RORC (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.

SUBMITTER: Cadenas C

PROVIDER: S-EPMC4613905 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loss of circadian clock gene expression is associated with tumor progression in breast cancer.

Cadenas Cristina C van de Sandt Leonie L Edlund Karolina K Lohr Miriam M Hellwig Birte B Marchan Rosemarie R Schmidt Marcus M Rahnenführer Jörg J Oster Henrik H Hengstler Jan G JG

Cell cycle (Georgetown, Tex.) 20140101 20

Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological par ...[more]

PMID: 25485508

Similar Datasets

Project description:ObjectiveTriple-negative (PR-, ER-, HER-2-) breast cancer (TNBC) is regarded as more aggressive and more likely to recur after medical care. Emerging evidence has demonstrated that the circadian clock system regulates cell-signaling pathways critical to cancer cell proliferation, survival and metastasis, meaning that it could be a good candidate for TNBC treatment. As such, the aim of the current study was to examine the molecular mechanism by which the circadian clock system contributes to cancer progression in TNBC.MethodsCancer cells and primary breast cancer tissues were immunostained for the measurement of circadian clock proteins (CLOCK, BMAL1 and PER1) and acetylserotonin methyltransferase (ASMT). The association between ASMT and clock proteins was assessed using siRNA and Western blot. Transwell assays were used to detect cancer cell migration and invasion while MTT assays were utilized to evaluate cell proliferation.ResultsCircadian clock proteins (CLOCK, BMAL1, and PER1) and ASMT expression were higher in TNBC and triple positive breast cancer (TPBC) compared with para-carcinoma tissues (PCTs). Intriguingly, there was an obvious correlation between circadian clock proteins and ASMT expression in both TPBC and TNBC. Similarly, circadian clock proteins and ASMT were expressed to a greater extent in BT-474 (triple-positive) cells than in MDA-MB-231 (triple-negative) cells. The inhibition of ASMT reduced circadian clock protein levels in both breast cancer cell lines. Further analysis showed that the expression levels of ASMT and circadian clock proteins did not correlate with clinical parameters such as age, tumor size, histologic grade and CK5/6, but increased significantly with lymphatic invasion in TNBC. In agreement with this finding, knockdown of ASMT significantly leads to reductions in migration and invasion in MDA-MB-231 cells. However, over-expression of CLOCK reversed the decreases seen in ASMT inhibited cells.ConclusionOur study suggests that ASMT regulates the circadian clock system in breast cancer and inhibition of ASMT reduces the invasiveness of triple-negative breast cancer cells by downregulating clock protein in a certain extent, indicating the potential value of ASMT as a drug target for TNBC treatment.

Project description:The circadian gene Timeless (TIM) provides a molecular bridge between circadian and cell cycle/DNA replication regulatory systems and has been recently involved in human cancer development and progression. However, its functional role in colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide, has not been fully clarified yet. Here, the analysis of two independent CRC patient cohorts (total 1159 samples) reveals that loss of TIM expression is an unfavorable prognostic factor significantly correlated with advanced tumor stage, metastatic spreading, and microsatellite stability status. Genome-wide expression profiling, in vitro and in vivo experiments, revealed that TIM knockdown induces the activation of the epithelial-to-mesenchymal transition (EMT) program. Accordingly, the analysis of a large set of human samples showed that TIM expression inversely correlated with a previously established gene signature of canonical EMT markers (EMT score), and its ectopic silencing promotes migration, invasion, and acquisition of stem-like phenotype in CRC cells. Mechanistically, we found that loss of TIM expression unleashes ZEB1 expression that in turn drives the EMT program and enhances the aggressive behavior of CRC cells. Besides, the deranged TIM-ZEB1 axis sets off the accumulation of DNA damage and delays DNA damage recovery. Furthermore, we show that the aggressive and genetically unstable 'CMS4 colorectal cancer molecular subtype' is characterized by a lower expression of TIM and that patients with the combination of low-TIM/high-ZEB1 expression have a poorer outcome. In conclusion, our results as a whole suggest the engagement of an unedited TIM-ZEB1 axis in key pathological processes driving malignant phenotype acquisition in colorectal carcinogenesis. Thus, TIM-ZEB1 expression profiling could provide a robust prognostic biomarker in CRC patients, supporting targeted therapeutic strategies with better treatment selection and patients' outcomes.

Dataset Information

Loss of circadian clock gene expression is associated with tumor progression in breast cancer.

Publications

Loss of circadian clock gene expression is associated with tumor progression in breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets