Author ORCID Identifier
https://orcid.org/my-orcid?orcid=0000-0001-5879-979X
Date of Award
2024
Document Type
Thesis (Ph.D.)
Department or Program
Cancer Biology
First Advisor
Todd W Miller
Second Advisor
Brock C Christensen
Abstract
Estrogen receptor-positive breast cancer remains one of the most frequently diagnosed cancers in women. Despite adjuvant endocrine therapy reducing the rate of recurrence, there remains a significant proportion of patients whose breast cancer will recur years to decades after the initial diagnosis. The underlying biology of tumor cells in the period between initiation of adjuvant therapy and recurrence is relatively unexplored, preventing the development of better treatment options. From a genome-wide screening approach, we identified and characterized broad metabolic reprogramming associated with the persistent cell state. We demonstrate that a decreased ability to metabolize glucose in turn pushes a higher reliance on oxidative phosphorylation. We uncovered additional consequences of metabolic shifts, namely increased levels of oxidative stress with depleted antioxidant reserves and increased reactive oxygen species. Coupled with an alteration in lipid profiles, specifically an increase in polyunsaturated phosphatidylethanolamine phospholipids, persisters were found to be highly sensitive to ferroptosis.
Our results led to the rational development of two novel treatment strategies to target persistent breast cancer cells. First, the observation of an increased reliance on oxidative phosphorylation led us to test a Complex I inhibitor in combination with endocrine therapy, which is synergistic in providing anti-cancer control. Second, the observation of an increased propensity for ferroptosis due to the confluence of factors contributing to the pro-oxidative state led us to test a ferroptosis inducer with endocrine therapy that provided superior anti-cancer effects. Together these studies provide evidence for further development of therapies to target metabolism as cancer treatments.
Recommended Citation
Tau, Steven, "IDENTIFICATION AND THERAPEUTIC TARGETING OF METABOLIC ALTERATIONS IN ESTROGEN RECEPTOR-POSITIVE BREAST CANCER" (2024). Dartmouth College Ph.D Dissertations. 278.
https://digitalcommons.dartmouth.edu/dissertations/278