Alternative Androgen Metabolism in Resistance to Aromatase Inhibitors.

Breast Cancer;Estrogens;Cytochrome P450;Oncology and Hematology;Pharmacy and Pharmacology;Health Sciences;Pharmacology

Sikora, Matthew JosephRuddon Jr, Raymond W. ;

University of Michigan

关键词: Breast Cancer;    Estrogens;    Cytochrome P450;    Oncology and Hematology;    Pharmacy and Pharmacology;    Health Sciences;    Pharmacology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/86575/mjsikora_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The treatment of estrogen-receptor positive breast cancer is based on endocrine therapy, with aromatase inhibitors (AIs) serving as the current front-line therapy in post-menopausal women. Despite prolonging disease-free survival, ~20% of patients receiving adjuvant AIS will relapse within 10 years of treatment initiation. Mechanisms of resistance to AI therapy remain unclear, and there is currently no way to predict which patients will benefit from AI therapy. We hypothesize that androgen metabolites generated independent of aromatase may induce breast cancer growth in the absence of primary estrogens. Thus the generation of alternative estrogens from precursor androgens represents a potential mechanism of resistance to AIs.This dissertation examines the ro9les of alternative pathways of testosterone metabolism that may generate estrogen-like steroids independent of aromatase. We show that the androgen metabolite 3βAdiol induces the proliferation of breast cancer cells through direct activation of ERα. In the absence of conventional estrogens during AI therapy, 3βAdiol may be an important mediator of estrogen-dependent breast cancer growth. Another pathway of testosterone metabolism, mediated by cytochrome P450 2B6, likely represents a mechanism of the clearance of testosterone by hydroxylation. Our observations with 3βAdiol led to the hypothesis that breast cancer cells maintained long-term in low estrogen concentrations may mimic conditions in patients on AI therapy. These models demonstrated that low concentrations of estrogens such as 3βAdiol promote novel estrogen-independent phenotypes. To improve studies of the role of steroidogenic enzymes from clinical trials sample sets, we also developed improved methods for genotype assessment from formalin-fixed paraffin-embedded tissues.These studies proved a basis for further clinical investigation into the tumo estrogen environment. Alternative estrogens represent a potential mechanism of AI resistance that can be targeted with novel therapeutic strategies. The advances made in this dissertation suggest that low estrogen concentrations promote unique mechanisms of AI resistance. Further, the adaptive response to low estrogen concentrations may confer resistance to targeted therapies. Identifying mechanisms of resistance, based in part on biomarkers that can be developed using the models described herein, will allow patients to be treated with therapies specifically targeted to their tumor, thereby improving clinical outcomes.