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Cancer patients experience circadian rhythm disruptions in activity cycles and cortisol release that correlate with poor quality of life and decreased long-term survival rates. However, the extent to which chemotherapy contributes to altered circadian rhythms is poorly understood. In the present study, we examined the extent to which paclitaxel, a common chemotherapy drug, altered entrained and free-running circadian rhythms in wheel running behavior, circulating corticosterone, and circadian clock gene expression in the brain and adrenal glands of tumor-free mice. Paclitaxel injections delayed voluntary wheel running activity onset in a light-dark cycle (LD) and lengthened the free-running period of locomotion in constant darkness (DD), indicating an effect on inherent suprachiasmatic nucleus (SCN) pacemaker activity. Paclitaxel attenuated clock gene rhythms in multiple brain regions in LD and DD. Furthermore, paclitaxel disrupted circulating corticosterone rhythms in DD by elevating its levels across a 24-hour cycle, which correlated with blunted amplitudes of Arntl, Nr1d1, Per1, and Star rhythms in the adrenal glands. Paclitaxel also shortened SCN slice rhythms, increased the amplitude of adrenal gland oscillations in PER2::luciferase cultures, and increased the concentration of pro-inflammatory cytokines and chemokines released from the SCN. These findings indicate that paclitaxel disrupts clock genes and behavior driven by the SCN, other brain regions, and adrenal glands, which were associated with chemotherapy-induced inflammation. Together, this preclinical work demonstrates that chemotherapy disrupts both central and peripheral circadian rhythms and supports the possibility that targeted circadian realignment therapies may be a novel and non-invasive way to improve patient outcomes after chemotherapy.

Circadian rhythms influence various aspects of biology, including hormonal, immunological, and behavioral processes. These 24-hour oscillations are necessary to optimize cellular functions and to synchronize these processes with the environment. Breast cancer patients and survivors frequently report disruptions in circadian oscillations that adversely affect quality-of-life, including fragmented sleep-wake cycles and flattened cortisol rhythms, which are associated with negative behavioral comorbidities (e.g., fatigue). However, the potential causal role of tumor biology in circadian dysregulation has not been investigated. Here, we examined the extent to which sham surgery, non-metastatic mammary tumors, or mammary tumor removal in mice disrupts circadian rhythms in brain clock gene expression, loco motor behavior (free-running and entrained), and physiological rhythms that have been associated with cancer behavioral comorbidities. Tumors and tumor resection altered time-of-day differences in hypothalamic expression of eight circadian-regulated genes. The onset of activity in entrained running behavior was advanced in tumor-bearing mice, and the amplitude of free-running rhythms was increased in tumor-resected mice. Tumors flattened rhythms in circulating corticosterone and Ly6c(Hi) monocytes which were largely restored by surgical tumor resection. This work implies that tumors alone may directly impact central and/or peripheral circadian rhythmicity in breast cancer patients, and that these effects may persist in cancer survivors, potentially contributing to behavioral comorbidities.

Cancer in humans alters circadian rhythms, including those of the immune system. Cancer patients display altered cortisol and immune cell rhythms, along with independent functional changes in immune cell proinflammatory cytokine responses. These altered immune/circadian effects are hypothesized to be due to cancer treatments, stress, and/or tumor physiology. Animal models indicate that tumors alone reorganize circadian metabolic control, body temperature, and corticosterone, but it is unknown whether immune rhythms are also influenced by tumors or whether potential circadian changes persist after tumor resection. This experiment tested the hypothesis that tumor resection attenuates tumor-induced alteration of circadian rhythms. Tumors were induced using non-metastatic mammary cancer cells, some were resected (“tumor-resect”) whereas others remained (“tumor”). Controls received sham surgery. Trunk blood was collected in all groups at zeitgeber time (ZT) 0, 6, 12, and 18 (n = 5–7/group/time). Whole blood was used to quantify immune populations using flow cytometry. Plasma was assessed for glucocorticoids using ELISA. Tumors increased the proportion and altered the circadian pattern of Ly6Chigh and Ly6Clow monocytes and neutrophils. Tumor resection attenuated the increased proportion of monocytes, but the dysrhythmia persisted. Tumors flattened corticosterone rhythms, which was tempered with tumor resections. Circadian rhythm behavioral data collection is underway. Taken together, persistent immune issues in survivors may be due, in part, to biological consequences of prior tumor exposure on circadian rhythms.