The characterization of estrogen receptor beta (ERβ) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERβ expression in cancer as compared with benign tumors or normal tissues, whereas ERα expression persists. The loss of ERβ expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERα target genes by ERβ or ERβ-specific gene induction could explain that ERβ has a differential effect on proliferation as compared with ERα. ERβ may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERα and ERβ expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.
A Bardin, N Boulle, G Lazennec, F Vignon, and P Pujol
C Knabbe and G Zugmaier
F Labrie, A Bélanger, L Cusan, C Labrie, J Simard, V Luu-The, P Diamond, J-L Gomez, and B Candas
An LHRH agonist was first administered to a prostate cancer patient 16 years ago in 1980 while combination therapy with an LHRH agonist and a pure antiandrogen was first administered 14 years ago in 1982. We take this opportunity to review briefly the events which, in our opinion, led to such fundamental changes in the endocrine therapy of prostate cancer. Following the observations of Huggins and his colleagues in 1941, orchiectomy and treatment with high doses of estrogens remained the standard therapy of prostate cancer for 50 years. Discovery of the structure of LHRH in 1971 by Schally and his colleagues stimulated the synthesis of highly potent analogs of LHRH with the objective of treating infertility. However, difficulties were met in finding the proper schedule of administration as well as the dose of LHRH agonists which could maintain stimulatory effects upon repeated administration. In fact, contrary to the expectations of a stimulatory effect, we found in 1977 that treatment of adult male rats with an LHRH agonist for a few days caused some inhibition of ventral prostate and seminal vesicle weight, although the inhibitory effects achieved were small compared with those of castration. It was then believed that the high serum LH levels induced by LHRH agonist treatment caused desensitization of the steroidogenic response in the testes.
Even more unexpected was the finding that of all the species studied, man was the most sensitive to the inhibitory action of LHRH agonists on testicular androgen biosynthesis and that medical castration could be easily achieved with LHRH agonists in adult men. In fact, a single intranasal administration of an LHRH agonist to healthy men in 1979 caused the expected acute rise in serum levels of testosterone and its precursors. This increase, however, was followed by a loss of diurnal cyclicity and lowered serum androgen levels which lasted for 3 to 4 days, thus suggesting that man is exquisitely sensitive to the inhibitory action of LHRH agonists. When, in 1980, the first prostate cancer patient received an LHRH agonist at the Laval University Medical Center, it was found that treatment with a high dose of the peptide caused a dramatic reduction in serum testosterone and dihydrotestosterone (DHT) after 2 weeks of administration. Contrary to the usual pattern in medical discoveries, the castration effect of LHRH agonists was first observed in men and not in experimental animals where castration is difficult or sometimes impossible to achieve with daily administration of LHRH agonists. A limitation to the use of LHRH agonists to achieve castration in prostate cancer patients was the temporary rise in serum testosterone and DHT at the start of treatment: such an elevation of serum androgens could cause an exacerbation of the symptoms or flare of prostate cancer. It was then decided to combine a pure antiandrogen with the LHRH agonist. In 1978, we found that the inhibitory effects observed in the rat with the combination of an LHRH agonist associated with a pure antiandrogen were more than additive, especially on seminal vesicle weight. These promising results suggested the use of a pure antiandrogen, not only to avoid the risk of disease flare during the first days of treatment with an LHRH agonist but also to offer the possibility of potentiating the inhibitory effects of the LHRH agonist on androgen-sensitive parameters.
Combination therapy with an LHRH agonist and a pure antiandrogen was first administered to a prostate cancer patient in March 1982, also at the Laval University Medical Center. The first patients with advanced prostate cancer treated with combination therapy in a non-randomized study showed a rapid fall in serum prostatic acid phosphatase and a marked improvement of the signs and symptoms of prostate cancer which were highly suggestive of the advantage of combination therapy compared with previous treatments. In fact, the first 58 stage D2 prostate cancer patients showed a positive objective response to combination therapy while a 94% rate of positive response was achieved in the total group of 260 patients entered in this first study. The highly promising results obtained in this initial study provided the stimulus for large-scale randomized and placebo-controlled clinical trials which confirmed the unique benefits of combination therapy on both duration of response and, most importantly, on survival. In fact, combination therapy became the first treatment shown to prolong life in prostate cancer and it has been the gold standard for the endocrine therapy of prostate cancer since 1989.
Since localized disease provides the only opportunity for cure of prostate cancer, the same combination therapy was next administered to patients at earlier stages of the disease. Randomized studies performed in patients with localized disease have recently demonstrated that combination therapy administered for 3 months before radical prostatectomy increases the proportion of patients having organ-confined disease by about 50% while the same approach associated with radiotherapy has been shown to delay the time to progression. Although the impact on survival of this neoadjuvant and adjuvant use of combination therapy, in association with radical prostatectomy or radiotherapy, remains to be assessed by long-term follow-up of the patients, it certainly raises the hope of a further significant improvement in the therapy of prostate cancer.
Since screening for prostate cancer with serum prostatic specific antigen is gaining wide acceptance, the diagnosis of prostate cancer is made at earlier stages of the disease where the reversibility of medical castration with LHRH agonists is the only acceptable approach. It has thus become clear that LHRH agonists should almost completely replace orchiectomy in the near future while there is no more valid reason to use treatment with estrogens because of their serious and life-threatening cardiovascular side-effects.
Knowledge of the structure of the genes responsible for the formation of DHT in the human prostate provides the scientific basis for the observation that about 50% of total androgens responsible for the growth of prostate cancer are synthesized in the prostatic tissue itself. Fortunately, prostate cancer is exquisitively sensitive to androgen deprivation, thus providing a powerful tool to control this cancer. The data summarized above indicate that the use of a pure antiandrogen in association with chemical castration represents the most acceptable approach to block androgen action maximally and thus cause maximal induction of cell cycle arrest and apoptosis in prostate cancer. Since the available antiandrogens still leave some free DHT in the prostatic tissue, research efforts should be directed to improving androgen blockade further with the development of more potent antiandrogens as well as efficient inhibitors of androgen formation. Simultaneously, efforts should be made to detect and treat prostate cancer at an earlier stage, when endocrine therapy alone or combined with radical prostatectomy or radiotherapy is clearly most efficient.
Endocrine-Related Cancer (1996) 3 243-278
V J Assikis and V C Jordan
R A Janknegt and T A Boon
Hormonal therapy alone for metastatic prostate cancer is effective in reducing tumour growth for a limited period of time. Progression of the tumour after an initial good response is due to the development of hormone-resistant cells. It is not known whether hormone-resistant cells develop as a mutation of the original hormone-sensitive cell later on in the progress of the disease or from early on as a separate entity. Chemotherapy has been used as second-line treatment with an average gain of only a few weeks over hormonal palliation. No studies of primary treatment with chemotherapy alone have been done. Some combined hormo-chemotherapy studies have shown some improvement in time to progression but not in survival
We have performed a multicentre randomized study comparing hormonal treatment (orchiectomy) versus hormo-chemotherapy (orchiectomy plus a high dosage of estramustin). This included 419 patients over 2 years: 281 M+ patients and 108 MO N+. The dosage of estramustin (Estracyt) was 840 mg/day (first month) and 560 mg/day thereafter.
The results showed that, in the M+ patients, median time to progression differed by 6 months for the hormo-chemotherapy-treated group (P=0.02). Median time to survival was not different in both groups, but multivariate analysis showed a 3-month difference in the group younger than 70 years in favour of the estramustin-treated group (P=0.0007). In the MO N+ patients, growth was slower. In both groups median time to progression and survival had not been reached after 35 months. Toxicity in the orchiectomy plus estramustin-treated group was low: there were no cardiovascular side-effects. Nausea was a problem during the first 4 weeks.
In our series pain and alkaline phosphatase were the main prognostic factors.
In conclusion, primary hormo-chemotherapy combined with estramustin showed a significant difference in time to progression (quality of life) but a limited survival benefit for a specific age group. In a future study we shall study patients with poor prognostic factors only.
Endocrine-Related Cancer (1996) 3 285-292
E Levin, S Caruso, and A M Actis
J Huber and D Gruber
Patients with macrocysts have a two- to fourfold higher risk of developing breast cancer and should be monitored carefully while on hormone replacement therapy. Estradiol and progesterone seem to enhance the mitotic rate of breast cells and serum levels should be reduced to the lowest levels possible. Investigations are necessary to confirm the stimulatory effect of serum steroids on breast/cyst epithelial cells. The effect of norethisterone on breast tissues must also be considered. The conversion of norethisterone to ethinylestradiol may make this progestogen unsuitable for replacement therapy in breast cyst patients, but this requires conformation in clinical studies.
Recently it was demonstrated that cholic acids accumulate in breast cyst fluid and that their metabolism is influenced by sex steroids. Experimental and clinical studies are necessary to elucidate this breast-gut connection.
L E Yaich, N Roodi, L R Bailey, C S Verrier, C J Yee, D R Cavener, and F F Parl
The estrogen receptor (ER) content of breast cancers predicts the likelihood of benefit from antiestrogen therapy. Tumors with an ER content of less than 10 fmol/mg are considered to be ER-negative and have a poor response rate to tamoxifen. The molecular basis of the ER-negative phenotype is not well understood. This study was conducted in five ER-positive (MCF-7, T47D, ZR-75-1, MDAMB-134, MDA-MB-361) and five ER-negative (BT-20, HBL-100, MDA-MB-157, MDA-MB-231, MDA-MB-468) human breast cancer cell lines to determine whether the ER-negative phenotype results from mutations in the coding region of the ER gene or is due to a deficiency of the transcriptional or post-transcriptional regulation of ER expression. The coding region was examined for mutations by denaturing gradient gel electrophoresis, single-strand conformation polymorphism and DNA sequence analysis. The presence and integrity of ER mRNA were investigated by Northern blotting and reverse transcription (RT)-PCR amplification. The presence and concentration of ER protein were assessed by Western blotting and hormone-binding assay. Both ER-negative and -positive cell lines contained silent mutations in codons 10, 325 and 594 of the ER gene, all of which probably represent neutral polymorphic sites. No missense or nonsense mutations were identified in any of the cell lines. About 2 kb of the 5′ upstream region and 4.3 kb of the 3′ untranslated region of the ER gene were present and grossly intact in all cell lines. By Northern blotting, ER mRNA was shown to be present in all ER-positive cell lines and, with the exception of BT-20 cells, absent in all ER-negative cell lines. However, ER mRNA was found to be detectable in all ER-negative cell lines when using the more sensitive RT-PCR. ER protein was undetectable by Western blotting in all cell lines that were ER-negative by ligand-binding assay. This study indicates that the ER-negative phenotype of breast cancer cell lines is not the result of ER gene mutations. It is due to the actual absence of ER protein which results from deficient ER expression at the transcriptional or post-transcriptional level.
Endocrine-Related Cancer (1995) 2 293-309
T Yamamoto, K Yokota, M Urabe, J Kitawaki, and H Honjo
The activity of estrone sulfatase (E1SF), which converts estrone sulfate to estrone, in uterine endometrial cancer tissue is remarkably high compared with endometrial tissues, and this is assumed to contribute to the growth of this tumor. Thus, in this study, in order to screen drugs for sulfatase inhibitor activity, the inhibitory effect of medroxyprogesterone acetate (MPA; which is widely used for advanced or recurrent endometrial cancer) on E1SF activity and steroid sulfatase (STS) gene expression in endometrial cancer cells was examined and compared with danazol (DZ).
MPA and DZ were shown to inhibit E1SF activity dose-dependently in the established endometrial cancer cell lines (Ishikawa and HEC-59 strains). These drugs (10−8 M) also inhibited the expression of STS mRNA, and this inhibition of STS gene expression is considered to partly explain their inhibitory actions against STS.
Endocrine-Related Cancer (1996) 3 337-340