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Aromatase Inhibitors As Potential Cancer Chemopreventives V Vol. 7, 65-78, Januar’, 1998 Cancer Epidemiology, Biomarkers & Prevention 65 Review Aromatase Inhibitors as Potential Cancer Chemopreventives Gary J. Kelloff,t Ronald A. Lubet, Ronald Lieberman, local estrogen production may be an alternative strategy, Karen Eisenhauer, Vernon E. Steele, James A. Crowell, as suggested by the discovery of a unique transcriptional Ernest T. Hawk, Charles W. Boone, and promoter of aromatase gene expression, 1.4, in breast Caroline C. Sigman adipose tissue. The development of drugs that target this Chemoprevention Branch, Division of Cancer Prevention and Control, promoter region may be possible. National Cancer Institute, Bethesda, Maryland 20852 1G. J. K., R. A. L., R. L.. V. E. S., J. A. C., E. T. H., C. W. B.l; and CCS Associates, Mountain View, Califomia 94043 1K. E., C. C. S.] Strategies in Development of Cancer Chemopreventive Agents This paper is the third in a series on strategies used by the Abstract Chemoprevention Branch of the National Cancer Institute to Epidemiological and experimental evidence strongly develop cancer chemoprevention drugs ( 1-3). One chemopre- supports a role for estrogens in the development and ventive strategy for hormone-dependent cancers is to interfere growth of breast tumors. A role for estrogen in prostate with the hormones that stimulate cellular proliferation in these neoplasia has also been postulated. Therefore, one tumors. Among the most important of these targets for inter- chemopreventive strategy for breast and prostate cancers vention are estrogen-responsive tumors. Estrogen production is to decrease estrogen production. This can be can be decreased by inhibiting aromatase, the enzyme cata- accomplished by inhibiting aromatase, the enzyme that lyzing the final, rate-limiting step in estrogen biosynthesis. The catalyzes the final, rate-limiting step in estrogen use of aromatase inhibitors is of clinical interest for cancer biosynthesis. The use of aromatase inhibitors is of clinical therapy, and selective, potent aromatase inhibitors have been interest for cancer therapy, and selective, potent developed. The rationale for use of aromatase inhibitors as aromatase inhibitors have been developed. Several of chemopreventives and identification of inhibitors to serve as these agents have demonstrated chemopreventive efficacy potential cancer chemopreventive agents are the subjects of this in animal models. review. The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to serve Association of Estrogen with Carcinogenesis as potential chemopreventive agents are the subjects of Breast. Aromatase, the enzyme that catalyzes the rate-limiting this review. After background information regarding step in estrogen formation (4), is expressed in several tissues in aromatase is presented, the data for each inhibitor are women. In premenopausal women, the granulosa cells of ovar- summarized separately. The discussion focuses on those ian follicles produce the majority of circulating estrogen, pri- inhibitors that are clinically available or in clinical trials, marily in the form of estradiol. Estrogen is also produced including: aminoglutethimide (Cytadren), rogletimide, extragonadally in liver, muscle, and fat by aromatization of fadrozole hydrochloride, liarozole hydrochloride, adrenal androgens. After menopause, adipose tissue is the ma- anastrozole (Arimidex), letrozole, vorozole, formestane, jor source ofcirculating estrogens (5). Extragonadal production exemestane, and atamestane. On the basis of results from of estrogen primarily involves aromatization of adrenal andro- preclinical studies, aromatase inhibitors may be stenedione, resulting in estrone, a weaker estrogen than estra- promising agents for clinical trials in populations at high diol (6). Epidemiological evidence strongly supports a role for risk for developing estrogen-dependent cancers. estrogens in the development and growth of breast neoplasia. Total suppression of aromatase may have adverse The most consistently documented epidemiological risk factors effects, as is evident in postmenopausal women (increased for breast cancer, early age at menarche, late age at menopause, osteoporosis, cardiovascular disease, and urogenital late age at first full-term pregnancy, and postmenopausal atrophy). However, on the basis of precinical studies of weight gain, all increase cumulative endogenous estrogen ex- chemopreventive efficacy and chemotherapeutic posure (7-9). Experimental evidence also strongly favors a role applications of aromatase inhibitors showing dose- for estrogens in the development and growth of breast cancers response efficacy, it may be possible to obtain ( 10, 1 1 ). Estrogens promote the development of mammary chemopreventive effects without total suppression of cancer in rodents and exert both direct and indirect proliferative aromatase and circulating estrogen levels. Suppressing effects on cultured breast cancer cells ( 1 1 ). Induction of en- zymes and proteins involved in nucleic acid synthesis (e.g., DNA polymerase and thymidine kinase) and oncogenes may account for their direct mitogenic effects. Indirect effects of Received 6/6/97; revised 9/29/97; accepted 10/15/97. The costs of publication of this article were defrayed in part by the payment of these hormones also occur via induction of pituitary prolactin page charges. This article must therefore be hereby marked advertisement in secretion and expression of various growth factors (e.g. , trans- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. forming growth factor a and epidermal growth factor) and I To whom requests for reprints should be addressed, at Chemoprevention non-growth factor peptides (e.g. , plasminogen activators). It Branch, Division of Cancer Prevention and Control, National Cancer Institute, Executive Plaza North, Suite 201, 6130 Executive Boulevard, Rockville, MD has been estimated that 30% of breast cancers are dependent on 20852. estrogen for their proliferation ( 1 2, 13). Although the available Downloaded from cebp.aacrjournals.org on September 23, 2021. © 1998 American Association for Cancer Research. 66 RevIew: Aromatase Inhibitors as Cancer Chemopreventives data are not conclusive, there is also evidence that estrogens induce regression of established tumors (e.g. , 28, 29) and, more may be directly genotoxic, for example, by DNA alkylation or importantly for the purposes of this discussion, prevent cancer oxidation, leading to free radicals, which, in turn, bind to and development (27, 30, 31). damage DNA (e.g., Ref. 14). Prostate. Etiological and risk factors for prostate cancer in- The estrogen that stimulates tumor growth can be derived dude age of >50 years, family history, high serum testoster- from extratumoral or tumor sources, and the relative impor. one, high-fat diet, prostatitis, and geographical background tance of each is controversial. Within the breast, adipose tissue (prevalence being highest in the United States, Canada, and is the major extratumoral source of aromatase, although aro- northwest Europe; Ref. 32). As for breast cancer, significant matase was also detected immunocytochemically in normal risk for prostate cancer appears to be associated with exposure breast epithelial cells in one study (15). Aromatase activity is to steroid hormones (i.e. , the high serum testosterone and high higher in adipose tissue from breast cancer patients than it is fat consumption). Besides testosterone, estrogens have also from those with benign breast disease (16). In breasts with been postulated to play a role in prostate cell proliferation and cancer, aromatase expression (17) and activity (18) are higher have been implicated in BPH and prostate cancer. BPH is a in quadrants bearing tumors compared with those without tu- nonmalignant enlargement of the prostate due to cellular hy- mors. The exact cellular localization of aromatase expression in perplasia and hypertrophy of both the epithelial and stromal breast cancer tissue is also somewhat controversial. Immuno- elements of the gland, whereas prostate cancer involves the cytochemical studies have detected aromatase in breast carci- epithelial tissue. Studies on the role of estrogen in BPH may be noma cells ( 15, 19) and in stromal spindle cells in breast tumors informative about the regulation of prostate cell proliferation, (20). At the present time, it appears that both adipose and breast but it should be emphasized that prostatic intraepithelial neo- tumor cells contribute to locally high estrogen production, and plasia, not BPH, is the most likely precursor of prostate carci- determination of their relative importance requires further noma (33, 34). study. In men, 10-25% of estrogen is synthesized locally in the The effects of estrogens are mediated by the ER.2 Al- testes, and 75-90% arises from extraglandular aromatization of though only a few studies have been carried out, 100% of testosterone and androstenedione (5, 35). The estrogen:andro- precancerous atypical hyperplastic ductal breast lesions that gen ratio increases with age, presumably due to greater estrogen have been studied express ER (21), and ER levels are higher in synthesis, accompanied by unchanged or decreased androgen atypical ductal hyperplasia than they are in normal breast epi- production. Whether the prostate is a source of estrogen is thelium (22). Changes in ER expression during tumor progres- controversial. Some studies have reported an absence of aro- sion are not well established,
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