TY - JOUR
T1 - Mammary tumors compromise time-of-day differences in hypothalamic gene expression and circadian behavior and physiology in mice
AU - Sullivan, Kyle A.
AU - Bever, Savannah R.
AU - McKim, Daniel B.
AU - Godbout, Jonathan P.
AU - Sheridan, John F.
AU - Obrietan, Karl
AU - Pyter, Leah M.
N1 - Funding Information:
The authors thank Dr. Dondrae Coble, Dr. Jessica C. Santos, Kelley Jordan, Lindsay Strehle, Browning Haynes, Austin Hilvert, and Kylie Wentworth for technical assistance. We also thank Jen Straten, Megan Fleming, and Richardo Hairston for animal care. This work was supported by The Ohio State University Wexner Medical Center , and NIH grants AG058109 (L.P.), CA216290 (L.P.), NS091302 (K.O.), and MH103361 (K.O.).
Funding Information:
The authors thank Dr. Dondrae Coble, Dr. Jessica C. Santos, Kelley Jordan, Lindsay Strehle, Browning Haynes, Austin Hilvert, and Kylie Wentworth for technical assistance. We also thank Jen Straten, Megan Fleming, and Richardo Hairston for animal care. This work was supported by The Ohio State University Wexner Medical Center, and NIH grants AG058109 (L.P.), CA216290 (L.P.), NS091302 (K.O.), and MH103361 (K.O.). The authors declare no competing interests.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8
Y1 - 2019/8
N2 - 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, locomotor 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 Ly6cHi 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.
AB - 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, locomotor 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 Ly6cHi 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.
KW - Cancer
KW - Circadian
KW - Corticosterone
KW - Entrainment
KW - Monocyte
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U2 - 10.1016/j.bbi.2019.05.028
DO - 10.1016/j.bbi.2019.05.028
M3 - Article
C2 - 31108169
AN - SCOPUS:85066124187
SN - 0889-1591
VL - 80
SP - 805
EP - 817
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -