Shiuan Chen

Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010

Received 12/18/97 Accepted 7/15/98

2. INTRODUCTION

Estrogens play an important role in breast cancer development. Approximately 60% of premenopausal and 75% of postmenopausal patients have estrogen-dependent carcinomas. The effects of estrogens on proliferation are mainly mediated by their interaction with the estrogen receptor (ER) (1). In estrogen-dependent breast tumors, estrogens are thought to induce the expression of peptide growth factors that are responsible for the proliferative responses of cancer cells (e.g., 2, 3). Aromatase, a cytochrome P450, is the enzyme that synthesizes estrogens by catalyzing three consecutive hydroxylation reactions converting C19 androgens to aromatic C18 estrogenic steroids (see figure 1). Aromatase converts androstenedione and testosterone to estrone and estradiol, respectively.

Figure 1. Aromatase converts androgens to estrogens

Aromatase is expressed in a tissue-specific manner. This enzyme is mainly expressed in the ovaries of premenopausal women. A very high level of aromatase is expressed in placenta in pregnant women. In postmenopausal women and men, adipose tissue and skin cells are the major sources of estrogen production, but the aromatase activity in these tissues is significantly lower than that in ovaries and the level of circulating estrogen is much lower in postmenopausal women and men than in premenopausal and pregnant women. Since aromatase is the enzyme responsible for the synthesis of estrogens, and estrogens play a major role in the development of breast cancer, abnormal expression of aromatase in breast cancer cells and/or surrounding adipose stromal cells, especially in postmenopausal women, may have a significant influence in breast tumor maintenance and growth in breast cancer patients. This review intends to summarize recent research from our and other laboratories in the area of aromatase expression and action in breast cancer tissue. Aromatase is expressed at a higher level in breast tumors and in situ estrogen biosynthesis has been shown to promote breast cancer growth in both an autocrine and a paracrine fashion. Studies related to these topics will be discussed in brief in this review (Sections 3 and 4). A major effort of our laboratory is to determine how aromatase expression in breast tumors is regulated. Gene regulation studies from our and other laboratories will be reviewed in Section 5. In addition, aromatase inhibitors are drugs used to treat breast cancer by suppressing in situ estrogen biosynthesis. The molecular basis of the interaction of various inhibitors with aromatase has been evaluated by site-directed mutagenesis, computer modeling, and inhibition kinetics. The findings on aromatase structure-function studies and inhibitor binding will be briefly summarized in Section 6. Finally, the potential effects of phytoestrogens and xenoestrogens on aromatase will be commented on in Section 7.