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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.

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Shelby M King, Tyvette S Hilliard, Lucia Y Wu, Randal C Jaffe, Asgerally T Fazleabas, and Joanna E Burdette

Ovarian cancer is the most lethal gynecological malignancy affecting American women. Current hypotheses concerning the etiology of ovarian cancer propose that a reduction in the lifetime number of ovulations decreases ovarian cancer risk. Advanced serous carcinoma shares several biomarkers with fallopian tube epithelial cells, suggesting that some forms of ovarian carcinoma may originate in the fallopian tube. Currently, the impact of ovulation on the tubal epithelium is unknown. In CD1 mice, ovulation did not increase tubal epithelial cell (TEC) proliferation as measured by bromodeoxyuridine incorporation and proliferating cell nuclear antigen staining as compared to unstimulated animals. In superovulated mice, an increase in the number of pro-inflammatory macrophages was detected in the oviduct. Ovulation also increased levels of phospho-γH2A.X in TEC, indicating that these cells were susceptible to double-strand DNA breakage following ovulation. To determine which components of ovulation contributed to DNA damage in the fallopian tube, an immortalized baboon TEC cell line and a three-dimensional organ culture system for mouse oviduct and baboon fallopian tubes were developed. TEC did not proliferate or display increased DNA damage in response to the gonadotropins or estradiol alone in vitro. Oxidative stress generated by treatment with hydrogen peroxide or macrophage-conditioned medium increased DNA damage in TEC in culture. Ovulation may impact the fallopian tube epithelium by generating DNA damage and stimulating macrophage infiltration but does not increase proliferation through gonadotropin signaling.

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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.

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Jaesung (Peter) Choi, Reena Desai, Yu Zheng, Mu Yao, Qihan Dong, Geoff Watson, David J Handelsman, and Ulla Simanainen

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

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T M Penning

Introduction Mammalian 17β-hydroxysteroid dehydrogenases (17β-HSDs) catalyze the final steps in male and female sex hormone biosynthesis. In the Leydig cells in the testis, 17β-HSD converts androst-4-ene-3,17-dione into the male sex hormone testosterone. In the ovary and placenta, 17β-HSD converts estrone (a weak estrogen) into 17β-estradiol (a potent estrogen) (Fig. 1). Deficiencies in testicular 17β-HSD have been associated with pseudohermaphroditism (Gross et al. 1986, Wilson et al. 1987, 1988, Farkas & Rosler 1993, Geissler et al. 1994), implicating the importance of this enzyme in testosterone production. It follows that inhibition of this enzyme could block androgen biosynthesis and androgen action. On this basis, selective inhibitors of testicular 17β-HSD have the potential to prevent the growth of androgen-dependent tumors, e.g. benign hyperplasia and cancer of the prostate. Moreover, effective inhibitors could be used as adjuvants to enhance the efficacy of androgen receptor antagonists. In human breast tissue, 17β-HSD is responsible
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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.

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W P Bocchinfuso and K S Korach

Introduction Estrogen has been thought to be required for the development, differentiation and function of the female reproductive tract (George & Wilson 1988). It promotes the proliferation of the uterine and vaginal epithelium and ovarian follicular development (Canez et al. 1992); the development of the mammary gland, external genitalia, appropriate reproductive sexual behavior, and other secondary sexual characteristics (George & Wilson 1988). In more non-traditional target tissues, estrogen action has been shown to influence bone development, lipid metabolism and cardiovascular function (Auchus & Fuqua 1994, Ciocca & Vargas Roig 1995). The biological actions of estrogens, particularly 17β-estradiol(estradiol), are mediated through the estrogen receptor, which functions as a ligand-inducible transcription factor and is a member of the nuclear receptor superfamily that bind steroids, thyroid hormone, retinoids, prostanoids and vitamin D1 (Tsai & O'Malley 1994). Like other nuclear receptors, the estrogen receptor is composed of distinct functional domains (Fig. 1)
Free access

Giorgio Secreto, Paola Muti, Milena Sant, Elisabetta Meneghini, and Vittorio Krogh

Five years of adjuvant therapy with anti-estrogens reduce the incidence of disease progression by about 50% in estrogen receptor-positive breast cancer patients, but late relapse can still occur after anti-estrogens have been discontinued. In these patients, excessive androgen production may account for renewed excessive estrogen formation and increased risks of late relapse. In the 50% of patients who do not benefit with anti-estrogens, the effect of therapy is limited by de novo or acquired resistance to treatment. Androgen receptor and epidermal growth factor receptor overexpression are recognized mechanisms of endocrine resistance suggesting the involvement of androgens as activators of the androgen receptor pathway and as stimulators of epidermal growth factor synthesis and function. Data from a series of prospective studies on operable breast cancer patients, showing high serum testosterone levels are associated to increased risk of recurrence, provide further support to a role for androgens in breast cancer progression. According to the above reported evidence, we proposed to counteract excessive androgen production in the adjuvant setting of estrogen receptor-positive patients and suggested selecting postmenopausal patients with elevated levels of serum testosterone, marker of ovarian hyperandrogenemia, for adjuvant treatment with a gonadotropins-releasing hormone analogue (medical oophorectomy) in addition to standard therapy with anti-estrogens. The proposed approach provides an attempt of personalized medicine that needs to be further investigated in clinical trials.

Free access

E Enmark and J Å Gustafsson

The recent discovery of a second estrogen receptor, ER&B;, shows that the mechanisms behind the effects of estrogen are far more complicated than previously assumed, and gives unique opportunities to gain a better understanding of these phenomena. ER&B; is expressed in many important target tissues for estrogen, and a better insight into the respective mechanisms of action of ERalpha and ER&B; might give clues concerning the etiology and pathogenesis of for example prostate or ovarian cancer. Development of ERalpha and ER&B; specific ligands may furthermore open up interesting new possibilities for treatment of e.g. postmenopausal symptoms and breast cancer. In this review, we will try to summarize what is known sofar about estrogen receptor &B;, with some emphasis on the human receptor and its expression. We will furthermore try so summarize what is known about different isoforms of the receptor, in view of what is known about isoforms and variants of other receptors, in particular estrogen receptor alpha (ERalpha) and the progesterone receptor (PR).

Acknowledgements

This study was supported by a grant from the Swedish Cancer Society.

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M C Pike, J R Daniels, and D V Spicer

Abstract

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