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Interactions between Prostaglandin E₂, Liver Receptor Homologue-1, and Aromatase in Breast Cancer

¹ Prince Henry's Institute of Medical Research; ² Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria, Australia; Departments of ³ Pathology and ⁴ Surgery, Tohoku University School of Medicine, Sendai, Japan

Requests for reprints: Colin D. Clyne, Prince Henry's Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. Phone: 61-3-9594-4372; Fax: 61-3-9594-6125; E-mail: colin.clyne{at}phimr.monash.edu.au.

Local synthesis of estrogens within breast adipose tissue by cytochrome P450 aromatase contributes to the growth of postmenopausal breast cancers. One of the major stimulators of aromatase expression in breast is prostaglandin E₂ (PGE₂) derived from tumorous epithelium and/or infiltrating macrophages. Recently, the orphan nuclear receptor, liver receptor homologue-1 (LRH-1), has also been shown to regulate aromatase expression in breast adipose tissue. We therefore examined the expression of, and correlations between, aromatase and LRH-1 mRNA in a panel of breast carcinoma tissues and adjacent adipose tissue. LRH-1 mRNA expression was low in normal breast tissue but markedly elevated in both breast carcinoma tissue and adipose tissue surrounding the tumor invasion (thereby paralleling aromatase expression). Laser capture microdissection localized the site of LRH-1 expression to tumor epithelial cells but not to intratumoral stromal cells. A strong correlation between LRH-1 and aromatase mRNA levels was observed in tumor-containing adipose tissue but not in tumor tissue. Ectopic expression of LRH-1 in primary human adipose stromal cells strongly activated endogenous aromatase mRNA expression and enzyme activity. Finally, treatment of adipose stromal cells with PGE₂ induced expression of both LRH-1 and aromatase. We suggest that PGE₂ derived from breast tumor tissue may increase aromatase expression in the surrounding adipose stroma in part by inducing LRH-1 in these cells. The roles of LRH-1 in breast cancer proliferation merit further study.

Key Words: breast cancer • aromatase • estrogen • LRH-1

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