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Tamoxifen Mediated Metabolic Stress: Molecular Mechanism And Therapeutic Opportunities, Natalie Ann Daurio
Publicly Accessible Penn Dissertations
Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER) positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacological and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMPK signaling pathway in vitro and in vivo. We also show that tamoxifen-induced cytotoxicity is modulated by ...