Author ORCID Identifier

https://orcid.org/0000-0002-0431-5654

Semester

Fall

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Psychology

Committee Chair

DeVries, A. Courtney

Committee Member

Nelson, Randy J.

Committee Member

Blank, Melissa D.

Committee Member

Weil, Zachary M.

Abstract

Neurobiological Variables Mediating the Relationship between

Breast Cancer and Sleep Disruption

Brittany D. Elliott, MS

Breast cancer is the most commonly diagnosed malignancy in women, with more than two million new cases diagnosed world-wide each year. Improvements in screening technology and diagnostics have increased survival rates, but cancer-associated sleep disruptions persist for the majority of breast cancer survivors well beyond the treatment period. In addition to reducing quality of life, reduced sleep quality is associated with greater incidences of affective dysfunction, reduced treatment efficiency, aggressive cancer progression, increased symptom severity, and increased mortality by all causes. Thus, identifying the variables mediating the relationship between breast cancer and sleep disruption remains a critical step in improving health outcomes for breast cancer survivors and served as the primary objective of this dissertation. A review of the literature regarding this relationship is provided in Chapter I.

Previous work from our lab has identified a potential role for tumor-induced increases in ghrelin in regulating sleep in mice expressing nonmetastatic 67NR mammary tumors. Ghrelin is produced in the stomach but binds to growth hormone secretagogue receptor one alpha (GHSR1a) to excite wake-promoting hypocretin/orexin (HO) neuronal activity. We have demonstrated that 1) sleep is disrupted in tumor-bearing mice, 2) these mice display aberrant HO activity, 3) ghrelin concentrations are increased in the serum of mice with tumors, and 4) 67NR cells express GHRL mRNA. Thus, the first aim of this dissertation was to investigate the functional relevance of ghrelin on sleep. In Chapter II, I employed a pharmacological and genetic manipulation to block increased ghrelin concentrations in mice with 67NR non-metastatic mammary tumors and measured sleep via wireless biotelemetry. Overall, no differences in serum ghrelin concentrations or HO neuronal activity were observed. When sleep-wake activity was compared between mid-to-late tumor progression, sleep increased for all mice during the light phase. However, during the dark phase in late tumor progression, 67NR tumor-bearing mice spent more time awake and mice bearing ghrelin knockout tumor spent more time in NREM sleep.

The second aim of this dissertation was to investigate the relationship between HO activity and sleep. As differences in serum ghrelin concentrations did not differ between groups in the previous studies, in Chapter III I assessed if ghrelin concentration varies as a function of tumor size by performing repeated blood sampling on days 15, 20, and 25 post tumor inoculation. Results from this study demonstrated an increase in ghrelin concentrations for 67NR tumor-bearing mice that returned to baseline by late tumor growth. To better understand the role of HO neuronal activity in sleep regulation, I used DREADDs technology to either inhibit or excite HO neurons and recorded sleep using noninvasive PiezoSleep recording software. Preliminary results suggest that chemogenetic manipulation may be a useful tool for investigating the role of HO activity in individuals with mammary cancer.

Whereas the first two aims examined the effects of mammary cancer on sleep, the third aim of this dissertation was to determine if sleep disruption alters factors associated with cancer development or progression. Findings from studies performed in rodents and humans demonstrate that exposure to dim light at night (dLAN) alters sleep, and research performed in adult populations suggests that dLAN exposure is associated with an increased risk of developing breast cancer. Sleep is an important regulator of immune, metabolic, and endocrine functions, which play key roles in both mammary gland development as well as tumorigenesis. Thus, Chapter IV includes an exploratory study that assessed the effects of dLAN exposure during development on factors contributing to breast cancer risk in adulthood. Exposure to dLAN did not alter mammary gland size, but was associated with changes in affective regulation after, but not prior to, tumor development in adulthood. Together, the studies described in this dissertation have contributed to our understanding of the reciprocal relationship between sleep disruption and breast cancer pathology.

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