Central mechanisms of glucocorticoid circadian rhythm dysfunction in breast cancer

Project Summary Breast cancer is still the most common malignancy in women worldwide. Despite the incredible advances made in the past decades towards eliminating breast cancer, nearly all women with metastatic breast cancer will succumb to the disease. Therefore, we desperately need new and improved approaches towards eliminating breast cancer. The proposed work focuses on a widely documented clinical finding with no known underlying mechanism: blunted circulating glucocorticoid rhythms in patients with breast cancer. Critically, patients with ‘flat’ or ‘blunted’ circadian rhythms in circulating glucocorticoids (e.g., cortisol) report lower quality of life and die from cancer earlier than patients with normal ‘robust’ circadian rhythms. Glucocorticoid rhythms are largely controlled by concerted interactions among the hypothalamus, pituitary, and adrenal glands (i.e., HPA-axis), and act to regulate diverse physiological processes essential for health including immune cell trafficking/polarization, energy mobilization, arousal, and synchronization of peripheral circadian clocks. Our preliminary data demonstrate that preclinical mouse models of breast cancer also exhibit this ‘blunting’ of the glucocorticoid rhythm, and this is accompanied by aberrant activity within hypothalamic neurons that regulate the HPA-axis (i.e., PVNCRH neurons). Additionally, by re-establishing a robust glucocorticoid rhythm via chemogenetic stimulation of these neurons, we were able to significantly impede primary breast cancer growth in mouse models. In the present proposal, we will systematically determine where along HPA-axis dysfunction occurs in response to breast cancer, identify the mechanism(s) driving this dysfunction, and then use orthogonal approaches to manipulate these mechanisms to confer benefits (reduced tumor and metastatic burden, enhanced responses to checkpoint blockade immunotherapy) in mouse models of breast cancer. These studies represent a significant step forward in our understanding of how malignant processes influence the host, and how host responses dictate cancer progression and therapeutic efficacy. These data will further inform the design of novel therapeutic approaches towards eliminating breast cancer by targeting the HPA-axis.