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Structure, Function and Inhibition of Aromatase

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Resistance to Aromatase Inhibitors in Breast Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 8))

Abstract

Human cytochrome P450 aromatase catalyzes with high substrate specificity the synthesis of estrogens from androgens. The crystal structure of human aromatase has revealed an androgen-specific active site. The structural insights have been utilized in the investigation of its transmembrane integration, roles of critical residues, reaction mechanism, implications of motion and flexibility on its function, ligand-binding interactions, and oligomeric states. Some of these results provide glimpses into the enzyme function as a membrane-embedded molecule. The structural and chemical basis of steroid-protein interactions have been harnessed to rationally design novel steroidal inhibitors with exclusive aromatase specificity. Several of these compounds exhibit superior inhibitory properties in purified human aromatase when compared with the breast cancer drug exemestane. The antiproliferative potencies of some of these compounds assayed in an MCF-7 breast cancer cell line exceed that of exemestane. The X-ray structures reveal that these new inhibitors exploit previously unknown aromatase-specific interactions. The newly developed structural and chemical biology knowledge lay the foundation for understanding the mechanisms of modulation of enzyme activity upon estrogen-dependent phosphorylation, and novel non-genomic aromatase-estrogen signaling feed-back reported in malignant breast cells as well as in neuroendocrine systems. The structural insights also provide the molecular basis for discovery of next generation inhibitors.

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Abbreviations

A:

Androstenedione

AI:

AROM inhibitor

ANZ:

Anastrozole

AROM:

Cytochrome P450 aromatase

CPR:

NADPH cytochrome reductase

E2:

17β-estradiol

ER:

Estrogen receptor

EXM:

Exemestane

LTZ:

Letrozole

mER:

Plasma membrane associated estrogen receptor

NMA:

Normal mode analysis

OR:

Opioid receptor

T:

Testosterone

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Acknowledgment

This work is supported in part by grant GM086893 from the National Institutes of Health.

No Conflict of Interest

We have no potential conflict of interest to disclose.

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Authors and Affiliations

  1. Department of Pharmacology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA

    Debashis Ghosh, Jessica Lo & Chinaza Egbuta

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  1. Debashis Ghosh
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  2. Jessica Lo
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  3. Chinaza Egbuta
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Correspondence to Debashis Ghosh .

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  1. Academic Laboratory of Medical Genetics, School of Clinical Medicine, Cancer Research UK Cambridge Institute, Statistics and Computational Biology Laboratory & University of Cambridge, Cambridge, United Kingdom

    Alexey Larionov

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Ghosh, D., Lo, J., Egbuta, C. (2015). Structure, Function and Inhibition of Aromatase. In: Larionov, A. (eds) Resistance to Aromatase Inhibitors in Breast Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-319-17972-8_3

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