Abstract
Circadian rhythm disruption can elicit the development of various diseases, including breast cancer. While studies have used cell lines to study correlations between altered circadian rhythms and cancer, these models have different genetic backgrounds and do not mirror the changes that occur with disease development. Isogenic cell models can recapitulate changes across cancer progression. Hence, in this study, a patient-derived breast cancer model, the 21T series, was used to evaluate changes to circadian oscillations of core clock protein transcription as cells progress from normal to malignant states. Three cell lines were used: H16N2 (normal breast epithelium), 21PT (atypical ductal hyperplasia), and 21MT-1 (invasive metastatic carcinoma). The cancerous cells are both HER2+. We assessed the transcriptional profiles of two core clock proteins, BMAL1 and PER2, which represent a positive and negative component of the molecular oscillator. In the normal H16N2 cells, both genes possessed rhythmic mRNA oscillations with close to standard periods and phases. However, in the cancerous cells, consistent changes were observed: both genes had periods that deviated farther from normal and did not have an anti-phase relationship. In the future, mechanistic studies should be undertaken to determine the oncogenic changes responsible for the circadian alterations found.
Highlights
The circadian clock is a hierarchical timing system that regulates physiological, behavioral, and metabolic functions across a 24 h day–night cycle and maintains temporal tissue homeostasis in coordination with the external environment [1,2]
The core clock consists of a well-characterized transcriptional–translational feedback loop (TTFL), where CLOCK and BMAL1 bind to an E-box promoter to drive the expression of other clock genes, including CRY and PER
H16N2 is derived from the normal epithelia, 21PT is derived from atypical ductal hyperplasia, and 21MT-1 is derived from the pleural effusion of lung metastasis [30]
Summary
The circadian clock is a hierarchical timing system that regulates physiological, behavioral, and metabolic functions across a 24 h day–night cycle and maintains temporal tissue homeostasis in coordination with the external environment [1,2]. Peripheral clocks are entrained by a central core clock located in the suprachiasmatic nucleus (SCN) and are necessary for normal tissue functioning, including cell development [3,4]. In particular, epidemiological studies have shown that long-term night shift workers have a higher risk of developing the disease [11,12,13]. Both in vitro and in vivo studies have indicated that mutation or dysregulation of clock genes can lead to the initiation of breast tumor growth and metastases [5,6,7,8]
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