Hijacking the Body’s Clock: How Breast Cancer Disrupts Brain-Regulated Rhythms

Breast cancer is increasingly recognized as a systemic disease that can disrupt the body’s physiological networks. Many patients experience chronic fatigue and sleep disruption, symptoms that are associated with loss of the normal daily rise and fall of glucocorticoid stress hormones (high in the morning and low at night) which help coordinate immune and metabolic function (1,2). Supported by the 2020 Breast Cancer Research Foundation-AACR NextGen Grant for Transformative Cancer Research, Jeremy C. Borniger, PhD, and colleagues showed that breast cancer can disrupt the time-of-day-specific brain signals that normally generate these hormone rhythms, with important consequences for antitumor immunity (3). In mouse models, restoring this normal neural timing slowed tumor growth and enhanced anti-tumor immunity, identifying circadian regulation as a promising therapeutic target and revealing a previously unrecognized brain-tumor communication pathway through which breast cancer reshapes systemic physiology.

An Assistant Professor at Cold Spring Harbor Laboratory, Dr. Borniger focuses on how the nervous system regulates systemic health in the context of malignancy. Enabled by the 2020 Breast Cancer Research Foundation-AACR NextGen Grant for Transformative Cancer Research, his team set out to address the gap in understanding how peripheral tumors influence central circadian control. “The funding I received from AACR was instrumental in getting this project off the ground and has supported my lab since I started in 2020,” said Borniger. “This initial support allowed me to hire additional researchers to build on preliminary data for subsequent funding applications that were ultimately successful.” The grant was pivotal in generating the initial hypotheses and complex datasets required to investigate how breast cancer tumors rewire hypothalamic circuits. Building on these discoveries, the team continues to advance the field of neuro-oncology.  

Under healthy conditions, circadian rhythms are regulated by the hypothalamic-pituitary-adrenal (HPA) axis, through the rhythmic firing of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. In their recent publication in Neuron (3), Dr. Borniger and his team observed weakened inhibitory signaling from the dorsomedial hypothalamus onto PVN CRH neurons in multiple breast cancer mouse models, resulting in chronic, mistimed activation of the stress-regulating circuit. This led to flattened glucocorticoid rhythms across the day, closely mirroring patterns seen in cancer patients. Using chemogenetic approaches to restore CRH neuron activity at the appropriate time, the researchers re-established normal hormone rhythms and directly tested how neural timing affects tumor growth and immune function.

Restoring circadian timing produced measurable biological benefits. Mice with corrected neural rhythms showed significantly slowed tumor progression and enhanced antitumor immunity, effects that depended on functional CD8+ T cells rather than direct hormone action on the cancer itself. In contrast, administering exogenous glucocorticoids without restoring their natural temporal pattern accelerated tumor growth. These results demonstrate that physiological timing, rather than hormone levels, is a critical determinant of disease outcome, redefining how stress biology interacts with cancer progression. “This research demonstrated a neural mechanism by which breast cancer in the body can reprogram host circadian rhythms to drive its own growth and evade immune destruction,” said Borniger. 

The findings reveal circadian timing as a powerful and previously underappreciated variable in cancer biology. By linking clinical observations of hormone rhythm disruption with mechanistic neuroscience, Dr. Borniger’s study expands the understanding of cancer progression and positions central neural timing as a key regulator of systemic disease behavior. The work also helps explain why disrupted glucocorticoid rhythms are associated with poor prognosis and suggests that restoring brain-regulated biological rhythms could complement existing cancer treatments.

Building on these AACR-supported discoveries, Dr. Borniger’s team continues to map the neural pathways connecting the brain to peripheral tumors and to identify additional neural targets that could be modulated to suppress tumor growth. Ultimately, the researchers aim to translate these insights to the clinic, exploring whether restoring natural hormone rhythms can improve outcomes for patients with breast cancer. By defining these brain-tumor communication pathways, his team opens the door to neuromodulation as a potential future companion to traditional cancer treatments.

References: 

1. Schmidt ME, Semik J, Habermann N, Wiskemann J, Ulrich CM, Steindorf K. Cancer-related fatigue shows a stable association with diurnal cortisol dysregulation in breast cancer patients. Brain Behav Immun. 2016;52:98-105. doi:10.1016/j.bbi.2015.10.005 

2. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst 2000;92(12):994-1000. doi:10.1093/jnci/92.12.994 

3. Gomez AM, Wu Y, Zhang C, Boyd L, Wee TL, Gewolb J, et al. Aberrant hypothalamic neuronal activity blunts glucocorticoid diurnal rhythms in murine breast cancer. Neuron 2026;114(5):820-835.e6. doi:10.1016/j.neuron.2025.11.019