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Article

Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment

Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois

Abstract

I. Introduction

A. The Aromatase Enzyme

B. The Aromatase (CYP19) Gene

C. Physiologic Regulation of Aromatase Expression in Human Tissues

D. Pathology Related to Aromatase Overexpression

II. Aromatase and Breast Cancer

A. Estrogen Formation in Breast Cancer

1. Aromatase in Adipose Tissue and Skin: Endocrine Effect.

2. Local Aromatase in Breast Cancer Tissue: Paracrine/Intracrine Effect.

B. Cellular Mechanisms That Regulate Aromatase Expression in Normal and Malignant Breast Tissue

1. Cellular Localization of Aromatase in Breast Cancer.

2. Inhibition of Adipogenic Differentiation in Breast Cancer: Link to Aromatase Overexpression.

C. Molecular Mechanisms Responsible for Elevated Aromatase Expression in Breast Cancer

1. Up-Regulation of Promoters I.3 and II.

2. Regulation of Promoters II and I.3 in MCF7 Cells.

3. Up-Regulation of Promoter I.7 in Breast Cancer.

D. Summary of Regulation of Aromatase Expression in Breast Cancer

E. Aromatase Inhibitors in the Treatment of Breast Cancer

III. Aromatase and Endometriosis

A. Mechanisms of Growth and Inflammation in Endometriosis

B. Definitions of Experimental Models and Abnormal Tissues in Women with Endometriosis

C. Estrogen Formation in Endometriosis

D. Cellular Mechanisms That Regulate Aromatase Expression in Eutopic Endometrium and Endometriosis

E. Prostaglandin E2 Biosynthesis and Action in Endometriosis

1. Prostaglandin E2 Biosynthesis in Endometrial Disease.

2. Prostaglandin E2 Action on Endometriotic and Endometrial Stromal Cells.

F. Molecular Mechanisms Responsible for Increased Expression of Steroidogenic Genes in Endometriosis

1. Up-Regulation of Promoter II for Increased Aromatase Expression.

2. Transcriptional Mechanisms Responsible for Increased Expression of the Aromatase Gene in Endometriosis.

G. Activation of Multiple Steroidogenic Promoters in Endometriosis

H. Summary of Regulation of Promoter II in Endometriotic Stromal Cells and Breast Adipose Fibroblasts

I. Aromatase Inhibitors in the Treatment of Endometriosis

IV. Aromatase and Endometrial Cancer

V. Aromatase and Uterine Fibroids (Leiomyomata)

A. Molecular Basis for Estrogen Dependence of Uterine Leiomyomata for Growth

B. Regulation of Estrogen Biosynthesis in Leiomyoma Smooth Muscle Cells

C. Aromatase Expression in Uterine Leiomyoma Tissues

D. Regulation of Aromatase Expression in Leiomyoma Tissues and Smooth Muscle Cells

E. Treatment of Uterine Leiomyomata with Aromatase Inhibitors

VI. Aromatase Excess Syndrome

A. Background and Clinical Manifestations

B. Genetic Basis for Familial Aromatase Excess Syndrome

C. Discussion on Gain-of-Function Mutations That Affect the Aromatase Gene

VII. Conclusions Regarding Aromatase Overexpression in Estrogen-Dependent Human Disease

A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues.

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