Volume 1155, Issue 1 p. 121-131

Regulation of Aromatase Expression in Breast Cancer Tissue

S.E. Bulun

S.E. Bulun

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

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Z. Lin

Z. Lin

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

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H. Zhao

H. Zhao

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

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M. Lu

M. Lu

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

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S. Amin

S. Amin

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

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S. Reierstad

S. Reierstad

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

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D. Chen

D. Chen

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

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First published: 26 February 2009
Citations: 61
Address for correspondence: Serdar E. Bulun, M.D., Northwestern University, Robert H. Lurie Research Bldg., Room 4-123, 303 E. Superior, Chicago, Illinois 60611, USA. Voice: +1-312-503-0520; fax: +1-312-503-0095. [email protected]

This work has been supported in part by the NCI grant CA67167 and grants from the AVON and Lynn Sage Foundations.

Abstract

Epithelial−stromal interactions play key roles for aromatase expression and estrogen production in breast cancer tissue. Upregulated aromatase expression in breast fibroblasts increases the tissue concentration of estradiol (E2), which then activates a large number of carcinogenic genes via estrogen receptor-α (ERα) in malignant epithelial cells. This clinically pertains, since aromatase inhibitors (AIs) are the most effective hormonal treatment of ERα-positive breast tumors. A single gene encodes aromatase, the key enzyme in estrogen biosynthesis, the inhibition of which by an AI effectively eliminates E2 production. Since alternative promoters regulated by distinct signaling pathways control aromatase expression, it is possible to target these pathways and inhibit estrogen production in a tissue-selective fashion. We and others previously found that the majority of estrogen production in breast cancer tissue was accounted for by the aberrant activation of the proximal promoter I.3/II region. PGE2 that is secreted in large amounts by malignant breast epithelial cells is the most potent known natural inducer of this promoter region in breast adipose fibroblasts. Signaling effectors/transcriptional regulators that mediate PGE2 action include the activator pathways p38/CREB-ATF and JNK/jun and the inhibitory factor BRCA1 in breast adipose fibroblasts. Selective inhibition of this promoter region may treat breast cancer while permitting aromatase expression via alternative promoters in the brain and bone and thus obviate the key side effects of the current AIs. The signaling pathways that mediate the regulation of the promoter I.3/II region in undifferentiated fibroblasts in malignant breast tumors are reviewed.