The idea of breast cancer prevention by hormonal means stemmed from the results of treatment trials, many of them carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP). Over the years, a number of NSABP treatment studies demonstrated that breast cancer recurrence was reduced in women with the disease who were given tamoxifen, a selective estrogen receptor (ER) modulator (SERM). Five subsequent tamoxifen prevention trials with this agent have shown a 48% reduction in ER-positive cancers, but no effect for ER-negative cancers, and an increase in endometrial cancer and thromboembolic events. The drug raloxifene, another SERM, originally examined as an osteoporosis agent, has also shown promise for the prevention of breast cancer, although, as with tamoxifen, the drug carries a risk for thromboembolic events. There is recent evidence in a large treatment trial that the aromastase inhibitor anastrazole, a 'pure anti-estrogen', holds promise as a breast cancer preventive agent. Longer follow-up and the testing of additional agents is required before these drugs can be used widely for prevention. In addition, future research should focus on the identification of at-risk women who can perhaps be targeted for specific prevention agents.
N Brünner, M D Johnson, C Holst-Hansen, J F Kiilgaard, E W Thompson, and R Clarke
M C Pike, J R Daniels, and D V Spicer
Epidemiological studies have consistently found that bilateral oophorectomy at a young age substantially reduces breast cancer risk. Such surgical menopause around age 35 has been found to reduce risk by 60 to 75%. A reversible medical oophorectomy using an agent such as a gonadotropin-releasing hormone agonist (GnRHA) should achieve a similar reduction in risk. Although the use of GnRHA alone is unacceptable because of the associated hypoestrogenic side-effects, these can be satisfactorily prevented by add-back low-dose estrogen treatment with intermittent progestin to protect the endometrium. It is estimated that a regimen of GnRHA plus add-back ultra low-dose estrogen and progestin would prevent some two-thirds of current breast cancer if used from age 30. If used from age 20 almost nine out of ten current breast cancer cases would be avoided. If, as is likely, these estimates also apply to women at high genetic risk of breast cancer because of possession of a BRCA1 or BRCA2 gene, their breast cancer risk would be reduced to below that of 'normal' women. The protective effects on ovarian cancer are calculated to be greater than the protective effects on breast cancer. Practical chemoprevention of breast and ovarian cancer using this approach should be possible within 5 years.
Endocrine-Related Cancer (1997) 4 125-133
B R Rao and B J Slotman
Ovarian cancer has a poor prognosis. At the time of diagnosis, in the majority of cases, the disease has progressed to a stage where intra-abdominal dissemination has already taken place. The pathogenesis of ovarian cancer is still unknown. However, epidemiologic studies have demonstrated that endocrine factors may play an important role. Elevated steroid hormone levels have been detected in ovarian cancer patients. The use of endocrine therapy, frequently consisting of progestins and/or tamoxifen, given on an empirical basis and as a last resort, has shown a modest response rate of 10-15%. About 50% of the tumors are positive for estrogen and progesterone receptors (PR). The PR status is a prognostic indicator, independent of the stage of disease, histology and patient's age. The majority of ovarian cancers (>70%) are positive for androgen receptors. Anti-androgens inhibit the growth of ovarian cancer cells in vitro in a majority of cases tested. Clinical trials to evaluate the efficacy of anti-androgen are recommended.
Endocrine-Related Cancer (1996) 3 309-326
Kellie L Jones and Aman U Buzdar
Breast cancer is the most common carcinoma diagnosed in women today excluding non-melanoma skin cancers. It has been well documented that estrogen plays a critical role in its development and is a major target for treatment. For many years, tamoxifen has been the gold standard for adjuvant hormonal therapy in breast cancer patients. With newer products targeting different mechanisms to suppress estrogen production, patients now have many decisions regarding their care. Agents such as luteinizing hormone releasing hormone (LHRH) agonists can suppress ovarian function in premenopausal patients and have been shown to be as effective and even better than chemotherapy (CMF — cyclophosphamide, methotrexate, fluorouracil-containing regimens) in certain patient populations. Tamoxifen continues to be an option as well as toremifene, a similar selective estrogen receptor modulator. With the advent of newer third generation aromatase inhibitors (anastrozole, letrozole and exemestane) toxicities have been documented to be less and in some cases they are more efficacious than the standard, tamoxifen. This article reviews the current data regarding ovarian suppression, ovarian suppression plus tamoxifen, tamoxifen, toremifene, anastrozole, letrozole, and exemestane in the treatment of adjuvant hormonal-sensitive breast cancer.
Petteri Ahtiainen, Victoria Sharp, Susana B Rulli, Adolfo Rivero-Müller, Veronika Mamaeva, Matias Röyttä, and Ilpo Huhtaniemi
The etiology of pituitary adenomas remains largely unknown, with the exception of involvement of estrogens in the formation of prolactinomas. We have examined the molecular pathogenesis of prolactin-producing pituitary adenomas in transgenic female mice expressing the human choriongonadotropin (hCG) β-subunit. The LH/CG bioactivity is elevated in the mice, with consequent highly stimulated ovarian progesterone (P4) production, in the face of normal estrogen secretion. Curiously, despite normal estrogen levels, large prolactinomas developed in these mice, and we provide here several lines of evidence that the elevated P4 levels are involved in the growth of these estrogen-dependent tumors. The antiprogestin mifepristone inhibited tumor growth, and combined postgonadectomy estradiol/P4 treatment was more effective than estrogen alone in inducing tumor growth. Evidence for direct growth-promoting effect of P4 was obtained from cultures of primary mouse pituitary cells and rat somatomammotroph GH3 cells. The mouse tumors and cultured cells revealed stimulation of the cyclin D1/cyclin-dependent kinase 4/retinoblastoma protein/transcription factor E2F1 pathway in the growth response to P4. If extrapolated to humans, and given the importance of endogenous P4 and synthetic progestins in female reproductive functions and their pharmacotherapy, it is relevant to revisit the potential role of these hormones in the origin and growth of prolactinomas.
Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women’s health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women’s health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.
Anna Konwisorz, Anette Springwald, Martina Haselberger, Regina Goerse, Olaf Ortmann, and Oliver Treeck
ICB-1 chromosome 1 open reading frame 38 (C1orf38) is a human gene initially described by our group to be involved in differentiation processes of cancer cells. Recently, we have reported ICB-1 as a novel estrogen target gene and identified an estrogen response element in its promoter. In this study, we examined the role of ICB-1 in regulation of proliferation of breast and ovarian cancer cells. We knocked down its expression in estrogen-dependent MCF-7 breast cancer cells and hormone-unresponsive SK-OV-3 ovarian cancer cells by stable transfection with a specific shRNA plasmid followed by G-418 selection. Knockdown of ICB-1 enabled a considerable estrogen response of SK-OV-3 cells in terms of proliferation. This transformation of SK-OV-3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor α (ERα) expression and a significant decrease of ERβ expression on the mRNA level. Expression of ERα-dependent genes progesterone receptor, pS2, fibulin 1c, and c-fos was elevated in SK-OV-3 cells stably expressing ICB-1 shRNA. In MCF-7 cells, ICB-1 knockdown exerted similar effects on gene expression, supporting a general role of ICB-1 in estrogen responsiveness. Our data suggest that differentiation-associated gene ICB-1 might exert antagonistic actions on cellular estrogen response, which can result in inhibition of estradiol-triggered proliferation. The molecular mechanisms mediating this inhibitory effect of ICB-1 on estrogen signaling are suggested to be limitation of ERα transcript levels but sustaining high levels of ERβ, reducing both activation of ERα target genes and cellular proliferation. The identification of ICB-1 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy.
Giorgio Secreto, Alessandro Girombelli, and Vittorio Krogh
The aim of this review is to highlight the pivotal role of androgen excess in the development of breast cancer. Available evidence suggests that testosterone controls breast epithelial growth through a balanced interaction between its two active metabolites: cell proliferation is promoted by estradiol while it is inhibited by dihydrotestosterone. A chronic overproduction of testosterone (e.g. ovarian stromal hyperplasia) results in an increased estrogen production and cell proliferation that are no longer counterbalanced by dihydrotestosterone. This shift in the androgen/estrogen balance partakes in the genesis of ER-positive tumors. The mammary gland is a modified apocrine gland, a fact rarely considered in breast carcinogenesis. When stimulated by androgens, apocrine cells synthesize epidermal growth factor (EGF) that triggers the ErbB family receptors. These include the EGF receptor and the human epithelial growth factor 2, both well known for stimulating cellular proliferation. As a result, an excessive production of androgens is capable of directly stimulating growth in apocrine and apocrine-like tumors, a subset of ER-negative/AR-positive tumors. The key role of androgen excess in the genesis of different subtypes of breast cancer has significant clinical implications for both treatment and prevention. Our belief stems from a thorough analysis of the literature, where an abundance of evidence is present to justify a clinical trial that would investigate the effectiveness of treating the underlying excessive androgen production.
Marc T Goodman, Galina Lurie, Pamela J Thompson, Katharine E McDuffie, and Michael E Carney
Although the role of estrogen in the etiology of ovarian cancer is uncertain, there is increasing evidence that hormone replacement therapy is a risk factor for ovarian malignancy. The production of estrogen involves the conversion of androgens via P450 aromatase, encoded by the CYP19A1 gene. Genetic variation in two CYP19A1 single-nucleotide polymorphisms (SNPs), rs749292 and rs727479, has been found to produce 10–20% increases in estrogen levels among postmenopausal women. We tested the hypothesis that these SNPs were associated with the risk of ovarian cancer in a population-based case–control study in Hawaii, including 367 histologically confirmed epithelial ovarian cancer cases and 602 age- and ethnicity-matched controls. The A allele of rs749292 was positively associated with ovarian cancer risk in a codominant model for all races combined (AG versus AA genotype: odds ratio (OR), 1.48 and 95% confidence interval (CI, 1.07–2.04); GG versus AA: OR, 1.87 (CI, 1.24–2.82); P trend=0.002). Similar significant associations of the rs749292 A allele on the risk of ovarian cancer were found among Caucasian and Japanese women. No relation of the rs727479 SNP to ovarian cancer risk was observed overall, although Caucasian women carrying the variant A allele compared with women with an CC genotype had an OR of 2.91 (CI, 1.15–7.37). These data suggest CYP19A1 variants may influence susceptibility to ovarian cancer.