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Structure, Regulation and Polymorphisms of the Aromatase Gene

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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 aromatase is widely expressed in various tissues and shows complicated regulation by both inductive and suppressive factors. The aromatase gene has the unique characteristic of having multiple exons available for use as exon 1, which are flanked with unique promoters. Tissue-specific expression of aromatase is regulated by alternative use of these exons. The exon 1 termed exon I.4 (1b) is the one that is mainly used in breast tissues. However, during cancer development it is often switched from exon I.4 (1b) to exon I.3 (1c) or exon PII (1d), which causes enhancement of aromatase expression in cancer-associated adipocytes and fibroblasts. The aromatase gene is further regulated at both the transcriptional and post-transcriptional levels through PKA-, PKC-, and tyrosine kinase receptor-mediated signaling pathways that employ prostaglandin E2 and class 1 cytokines. Epigenetic modifications of the aromatase gene and microRNA-mediated aromatase regulation may play a critical role in breast cancer progression. Several genetic polymorphisms in the aromatase gene may be prognostic factors of disease and may influence response to aromatase inhibitors.

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Abbreviations

AP-1:

Acivator protein-1

ATF-2:

Activating transcription factor-2

CAA:

Carcinoma-associated adipocytes

CAF:

Carcinoma-associated fibroblasts

C/EBP:

CCAAT/enhancer binding protein

CRE:

cAMP-responsive element

CREB:

CRE binding protein

E2:

17β-estradiol

ERK:

Extracellular signal-regulated kinase

GAS:

γ-interferon activation site

GPER:

G protein-coupled estrogen receptor

GRE:

Glucocorticoid responsive element

IHC:

Immunohistochemical staining

LRH-1:

Liver receptor homologue-1

MAPK:

Mitogen-activated protein kinase

PGE2 :

Prostaglandin E2

PI3K:

Phosphoinositide 3-kinase

PKA:

Protein kinase A

PKC:

Protein kinase C

PPAR:

Peroxisome proliferator-activated receptor

RT-PCR:

Reverse transcriptase-polymerase chain reaction

SF-1:

Steroidogenic factor-1

SNP:

Single nucleotide polymorphism

Sp1:

Specificity protein 1

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Nobuhiro Harada

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Correspondence to Nobuhiro Harada .

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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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Harada, N. (2015). Structure, Regulation and Polymorphisms of the Aromatase Gene. 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_2

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