A brain-body feedback loop driving HPA-axis dysfunction in breast cancer.

Area of Science:

• Neuroscience
• Endocrinology
• Immunology

Background:

• Disrupted circadian rhythms in glucocorticoids (GCs) are observed in breast cancer patients, correlating with poorer outcomes.
• The precise cause of GC rhythm disruption in breast cancer remains unclear, with potential factors including treatment, stress, and comorbidities.
• Primary breast cancer itself may directly impact the neuroendocrine system regulating GCs.

Purpose of the Study:

• To investigate whether primary breast cancer alone disrupts host glucocorticoid rhythms.
• To determine the neural mechanisms underlying GC rhythm disruption in breast cancer.
• To explore the therapeutic potential of neuromodulating hypothalamic neurons to restore GC rhythms and impact tumor growth.

Main Methods:

• Utilized mouse models of mammary tumors to assess glucocorticoid rhythms and hypothalamic neuronal activity.
• Measured synaptic activity and neuronal firing in paraventricular hypothalamic corticotropin-releasing hormone (PVN ^CRH) neurons.
• Employed chemogenetics (hM3Dq) to stimulate PVN ^CRH neurons at specific circadian phases and evaluated tumor progression and anti-tumor immunity (CD8+ T cells).

Main Results:

• Mammary tumors blunted host GC rhythms and increased activity in PVN ^CRH neurons, even before tumors were palpable.
• Tumor-bearing mice showed reduced inhibitory synapses on PVN ^CRH neurons, leading to net neuronal excitation and impaired negative feedback on GC production.
• Circadian phase-specific stimulation of PVN ^CRH neurons restored normal GC rhythms, reduced tumor progression, and enhanced the presence of effector CD8+ T cells within tumors.

Conclusions:

• Primary breast cancer disrupts the hypothalamic-pituitary-adrenal (HPA) axis by disinhibiting PVN ^CRH neurons, leading to altered GC rhythms.
• Therapeutic neuromodulation of PVN ^CRH neurons, timed to specific circadian phases, can mitigate breast cancer progression.
• The anti-tumor effects of PVN ^CRH neuronal stimulation are mediated, at least in part, by enhancing CD8+ T cell-dependent anti-tumor immunity.