Effects of Metabolic Reprogramming Interventions on Triple-Negative Breast Cancer Cells Public Deposited

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  • September 30, 2019
  • Ho, Alyssa
    • Affiliation: Gillings School of Global Public Health
  • TNBCs comprise approximately 15-20% of all BC cases and are defined by their lack of expression of estrogen receptors, progesterone receptors, and excess HER2 protein. There are currently no approved targeted therapies available for patients with TNBC other than cytotoxic chemotherapy, resulting in elevated rates of cancer recurrence, metastasis, and mortality. A promising area in nutrition and cancer research, with the potential to improve cancer outcomes, is dietary modification such as caloric restriction (CR) which has been shown to reduce tumor incidence, progression, and sensitization to some chemotherapeutic agents in preclinical TNBC murine models. While dietary interventions have shown promise for improving cancer outcomes in murine models, translating these approaches to humans has proven difficult. Major issues include a low tolerance of extreme diets (feasibility) and concerns about safe use of these interventions in cancer patients. Additionally, in response to the decrease in external nutrients and pro-growth signals during a fasting or CR state, cancer cells can generate energy by breaking down damaged cellular components to maintain homeostasis and viability through the process known as autophagy. Autophagy benefits cancer cells fighting for survival in nutrient-poor conditions, promoting tumor growth and, in some cases, metastasis. Our objective is to identify pharmacologic approaches, or metabolic reprogramming interventions (MRIs), which can be combined in innovative ways to recapitulate some or most of the beneficial effects of the previously mentioned dietary interventions. Moreover, we posit that the increased dependence on autophagy observed in fasting/CR can be exploited to improve efficacy of autophagy inhibitors – which are currently being tested in clinical trials for TNBC - and existing chemotherapies. Specifically, the purpose of this project is to examine the separate and combined effects of autophagy-inducing MRIs, autophagy inhibition, and carboplatin on murine TNBC progression.
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