T M Penning
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
P Feuillan, D Merke, E W Leschek, and G B Cutler Jr
During puberty, estrogen causes breast maturation and growth of the uterine lining in girls, and accelerates linear growth and bone maturation in both boys and girls. Decreasing the biosynthesis of estrogen can attenuate these processes. In 12 girls with the McCune-Albright syndrome (MAS), in which precocious puberty is due to production of estrogen from ovarian cysts, testolactone (40 mg/kg per day) decreased the volume of ovarian cysts, the frequency of menses, and the rates of growth and bone maturation, for periods of 1-4 years. In a 6-month pilot study of 12 children (eight boys; four girls) with congenital adrenal hyperplasia, testolactone, in combination with an antiandrogen (flutamide), a mineralocorticoid (fludrocortisone acetate, Florinef), and a reduced glucocorticoid dose, improved the control of growth and bone maturation compared with conventional therapy. In a 6-year study of 10 boys with familial male precocious puberty, testolactone, in combination with an antiandrogen (spironolactone), decreased rates of growth and bone maturation, and increased predicted adult height. All patients who developed evidence for gonadotropin-dependent puberty were also treated with a GnRH analog. Testolactone had no important adverse effects in any group of patients, although the need for a four-times-daily dosing schedule made compliance difficult for many families. We conclude that suppressing of estrogen with testolactone was effective therapy, and that more potent and specific inhibitors of aromatase could further improve the treatment of these disorders.
S Chen, D Zhou, T Okubo, Y C Kao, and C Yang
Aromatase has been shown to be expressed at a higher level in human breast cancer tissue than in normal breast tissue, by means of enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture including MCF-7 breast cancer cells, animal experiments using aromatase-transfected breast cancer cells, and transgenic mouse studies have demonstrated that estrogen production in situ plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase is believed to be able to stimulate breast cancer growth through both autocrine and paracrine pathways, as demonstrated by a three-dimensional cell culture study. RT-PCR and gene transcriptional studies have revealed that the aromatase promoter is switched from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancerous tissue. Recently, we identified and characterized a cAMP-responsive element (CREaro) upstream from promoter I.3 by DNA deletion and mutational analyses. Our results from promoter functional analysis also demonstrated an interaction between the CREaro and the silencer element (S1) that was identified previously in our laboratory. In the presence of cAMP, the positive regulatory CREaro can overcome the action of the silencer on the function of promoter I.3. On the basis of results generated from our own and other laboratories, we propose that, in normal breast adipose stromal cells and fibroblasts, aromatase expression is driven by promoter I.4 (glucocorticoid dependent), and that the action of promoters I.3 and II is suppressed by the silencer negative regulatory element. However, in cancer cells and surrounding adipose stromal cells, the cAMP level increases, and aromatase promoters are switched to cAMP-dependent promoters - I.3 and II. Furthermore, we applied the yeast one-hybrid screening method to search for proteins interacting with the silencer element, S1. The major protein identified was ERRalpha-1; however, SF-1, which is present in the ovary, is not detected in breast cancer tissue. Using a reporter plasmid with the aromatase genomic fragment containing promoter I.3 and S1, in breast cancer SK-BR-3 cells, ERRalpha-1 was found to have a positive regulatory function. It is believed that the silencer element in the human aromatase gene may function differently in different tissues, as a result of distinct expression patterns of transcription factors.
G Scambia, G Ferrandina, G D'Agostino, A Fagotti, M Di Stefano, F Fanfani, F G Serri, and S Mancuso
Ovarian cancer accounts for 5% of all cancer deaths in Western countries and is the most frequent cause of gynaecologic cancer mortality. The incidence varies with age between 1% and 14% with a peak rate in the eighth decade, and in the majority of cases, the disease has already spread beyond the pelvic cavity at time of diagnosis. Although in the last decades the introduction of cisplatin-based chemotherapy resulted in an improvement of patient survival, the percentage of recurrent disease is high even in those patients who achieve a complete response to chemotherapy, so that more than 80% of patients with advanced stage of disease die within 5 years (Copeland & Gershenson 1986). At present the prognostic characterisation of ovarian cancer patients, based on clinico-pathological parameters, such as stage, histology, grade and residual tumour after surgery, seems to be inadequate, since patients with similar clinico- pathological characteristics often experienced different clinical outcome. Therefore, the identification of biological factors related to tumour aggressiveness could be relevant in order to identify patients with different prognosis and chance to respond to chemotherapy, thus allowing the selection, at time of initial diagnosis, of high risk patients needing more aggressive therapy or alternative treatment, and a closer follow-up. Among the biological parameters proposed as possible prognostic factors in ovarian cancer much attention has been focused on endocrine factors and especially on steroid hormones and their receptors. Although several epidemiological and in vitro evidences have demonstrated that, similarly to breast and endometrial cancer, ovarian cancer cell biology could be influenced by the biochemical pathways promoted by the interaction of estrogens and progesterone with their specific receptors (ER, PR) conflicting data have been reported about the possible clinical role of ER and PR in this neoplasm. This review is aimed: a) to summarise the informations about the influence of steroid hormones and their receptors in the biology of ovarian cancer in in vitro models as well as in primary tumours;b) to investigate the association of steroid hormone receptor expression with the clinico-pathological parameters and the clinical outcome in ovarian cancer patients.c) to report the data of the literature about the rationale and the results of endocrine therapy in ovarian cancer.
H Sasano, S Sato, K Ito, A Yajima, J Nakamura, M Yoshihama, K Ariga, T J Anderson, and W R Miller
It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.
G Olt and R Mortel
Oliver Zierau, Jacintha O’Sullivan, Colm Morrissey, Dana McDonald, Winfried Wünsche, Martin R Schneider, Martin P Tenniswood, and Günter Vollmer
Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated.
We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals.
Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.
E M Rosen, S Fan, and C Isaacs
The breast and ovarian cancer susceptibility gene-1 (BRCA1) located on chromosome 17q21 encodes a tumor suppressor gene that functions, in part, as a caretaker gene in preserving chromosomal stability. The observation that most BRCA1 mutant breast cancers are hormone receptor negative has led some to question whether hormonal factors contribute to the etiology of BRCA1-mutant breast cancers. Nevertheless, the caretaker function of BRCA1 is a generic one and does not explain why BRCA1 mutations confer a specific risk for tumor types that are hormone-responsive or that hormonal factors contribute to the etiology, including those of the breast, uterus, cervix, and prostate. An accumulating body of research indicates that in addition to its well-established roles in regulation of the DNA damage response, the BRCA1 protein interacts with steroid hormone receptors (estrogen receptor (ER-α) and androgen receptor (AR)) and regulates their activity, inhibiting ER-α activity and stimulating AR activity. The ability of BRCA1 to regulate steroid hormone action is consistent with clinical-epidemiological research suggesting that: (i) hormonal factors contribute to breast cancer risk in BRCA1 mutation carriers; and (ii) the spectrum of risk-modifying effects of hormonal factors in BRCA1 carriers is not identical to that observed in the general population. These data suggest a model for BRCA1 carcinogenesis in which genomic instability leads to the initiation of cancerous cell clones, while loss of normal restraint on hormonal stimulation of mammary epithelial cell proliferation allows amplification of these pre-existing clones. Further research will be required to substantiate this hypothesis.
Francesmary Modugno, Robin Laskey, Ashlee L Smith, Courtney L Andersen, Paul Haluska, and Steffi Oesterreich
Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence from in vitro studies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response.