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PubMed2001

Effects of estrogenic compounds on human spermatozoa: evidence for interaction with a nongenomic receptor for estrogen on human sperm membrane.

Estrogens play an important role in the development and regulation of the male reproductive system. We have earlier shown that a nongenomic receptor for estradiol present on sperm plasma membrane mediates the effects exerted by this hormone on sperm intracellular calcium concentrations ([Ca(2+)](i)), as well as on the biological response to progesterone (P). In particular, 17 beta-estradiol (17betaE(2)) shows an inhibitory effect on P-mediated calcium influx and acrosome reaction (AR). In the present study, the effects of different anti-estrogens and xenoestrogens on [Ca(2+)](i) and AR stimulated by P have been investigated in human spermatozoa in order to better define the pharmacological characteristics of the sperm membrane estrogen receptor. The anti-estrogens tamoxifen (Tx) and ICI 164384 (ICI) induce only a slight increase of [Ca(2+)](i), which, however, as in the case of 17betaE(2), results in a reduction of P-stimulated calcium influx. Moreover, both the compounds reduce the calcium response to 17betaE(2) without affecting 17betaE(2)-inhibition of calcium response to P. Concerning AR, Tx alone does not alter either spontaneous or P-stimulated AR but partially revert the inhibitory effect of 17betaE(2). These results indicate that the two estrogens act as pharmacological agonists of the membrane estrogen receptors of human spermatozoa. On the other hand, the xenoestrogens bisphenol A (BPA) and octyiphenol polyethoxilate (OP) do not exert any direct effect on calcium fluxes and AR in human spermatozoa either in basal conditions or in response to P challenge. Moreover, although these environmental estrogens have been suggested to mimic estrogen effects in the other cell types, probably acting through genomic receptors, in human spermatozoa they do not interfere with 17betaE(2) binding to its membrane receptor and with the short-term effects exerted by this steroid. In conclusion, our data indicate that the membrane receptor for estradiol in human spermatozoa shows both biochemical and pharmacological differences respect to the genomic receptor.

Acrosome Reaction↗
PubMed2001

Direct effects of GnRH agonists in human hormone-sensitive endometrial cells.

The antiproliferative effect of two GnRH agonists (leuprorelin acetate and triptorelin), alone or combined with tamoxifen (TAM) or medroxyprogesterone acetate (MPA), on human estrogen-sensitive endometrial cancer cells (Ishikawa) was investigated. Although ineffective when tested alone in all the culture conditions used, both analogues counteracted or even suppressed the estrogen-stimulated growth of Ishikawa cells. The antiestrogenic effect of TAM or MPA was not modified by their association with high doses of the GnRH analogues, but low concentrations of triptorelin combined with MPA 10(-7) M determined a reduction in cell numbers which was greater than that obtained with the progestin or the analogue alone. In addition, analogue treatment prevented the estrogen-induced decrease in the level of estrogen receptors. Our data provide evidence that GnRH agonists can directly inhibit estrogen-stimulated endometrial cancer cell growth and suggest that they may interfere with steroid-receptor machinery.

Antineoplastic Agents, Hormonal↗
PubMed2004

Estrogen in cardiovascular disease.

PURPOSE OF REVIEW: The controversy surrounding hormone replacement therapy has induced fear in patients and left many researchers with the impression that estrogen produces negative effects on cardiovascular function. The aim of this review is to summarize recent findings illustrating that estrogen also has positive effects even if estrogen replacement therapy is not a cure-all. RECENT FINDINGS: Studies have unveiled new aspects of estrogen action in the cardiovascular system; however, clinical trials have not demonstrated a protective effect of the most widely used modalities of hormone replacement therapy against cardiovascular disease. New information has emerged showing that estrogen has both beneficial and detrimental effects. Further mechanistic studies and use of well defined forms of estrogens and selective estrogen receptor modulators will continue to provide novel mechanistic information that will likely lead to the development of new avenues for therapeutic interventions. SUMMARY: Estrogens, like other steroid hormones, are potent actors in the cardiovascular system. Since half the population have high levels of estrogen most of their lives it is plain that estrogen has a variety of beneficial physiologic functions. Clinical studies, however, have demonstrated that a specific formulation of a combination of potent estrogens and metabolites is not a magic bullet, but induces both positive and negative impacts on different organ systems. More research into the mechanistic actions of estrogens in specific pathways in individual cell types is necessary to determine appropriate therapeutic interventions to replace the loss of positive effects of estrogens while minimizing the negative effects in postmenopausal women.

Animals↗
PubMed1999

Sonographic assessment of the endometrium in osteopenic postmenopausal women treated with idoxifene.

Idoxifene is a novel selective estrogen receptor modulator that has shown beneficial effects on bone turnover and lipid metabolism in clinical studies. Preclinical studies have demonstrated that idoxifene has estrogen antagonist activities on the endometrium. This paper describes the results of a double-blind, placebo-controlled, and dose ranging study involving 331 osteopenic postmenopausal women who were treated with either placebo or idoxifene (2.5, 5, or 10 mg/day) for 12 weeks. In these women, endometrial assessment was carried out by transvaginal sonography and endometrial biopsy on selected patients at baseline and on all women at the end of treatment. Women with an endometrial thickness greater than 10 mm were excluded from the study. Aspiration endometrial biopsy was performed on women with an endometrial thickness between 6 and 10 mm at baseline and on all women after treatment. Of the 298 biopsies performed in the subjects at the end of treatment, 99% of the women were reported to have either a benign or atrophic endometrium (85%) or insufficient tissue for diagnosis (14%). Proliferative histologic features were reported in two cases (1%) (2.5 mg idoxifene) and atypical hyperplasia in one placebo patient. Even though idoxifene use was associated with a dose related increase in endometrial thickness as evaluated by transvaginal sonography, no relationship was established between endometrial histologic features and change in endometrial thickness. On histologic analysis, the increase in endometrial thickness seen on transvaginal sonography was not associated with proliferative or hyperplastic change in the epithelial (glandular) endometrial tissue. In 48 patients (16% of total) transvaginal sonography showed endometrial thickening of 5 mm or more over the study period. The endometrial histologic features were benign in all these patients. Nineteen percent of women developed intraluminal fluid, even though endometrial thickness was normal and unchanged and histologic features were normal. Our data show that after 3 months of treatment, no significant pathologic changes of the endometrium were observed. Our data indicate that measurements of endometrial thickness by transvaginal sonography may falsely suggest the presence of endometrial pathologic changes in some postmenopausal women treated with idoxifene. Additional testing using saline infusion sonohysterography is an important part of the transvaginal sonography protocol in equivocal or abnormal cases to exclude focal lesions such as polyps. In addition, our data indicate that pathologic changes of the endometrium are extremely rare in the treated group, indicative of its short term safety. Continued investigation such as this will be needed to establish long term safety.

Aged↗
PubMed2000

Recombinant cell bioassays for endocrine disruptors: development of a stably transfected human ovarian cell line for the detection of estrogenic and anti-estrogenic chemicals.

The ability of a variety of compounds to disrupt normal endocrine homeostasis, and potentially, the physiological and reproductive capacity of an organism, has gained worldwide attention in recent years. In an attempt to identify such compounds, and to examine the mechanism(s) by which they may exert their actions, we have constructed reporter plasmid vectors that contain the firefly luciferase gene under hormone-inducible control of estrogen-, androgen-, or retinoic acid-responsive DNA enhancer elements. Transient transfection of these vectors into appropriate receptor-containing cell lines revealed their ability to respond to their respective hormones with the induction of luciferase. Here, we describe development and optimization of a recombinant human ovarian carcinoma (BG-1) line, which has been stably transfected with the estrogen responsive luciferase reporter plasmid. The resulting recombinant cell line (BG1Luc4E(2)) responds to 17beta-estradiol at concentrations as low as 1 pM. The utility of BG1Luc4E(2) cells as a bioassay screening system for environmental estrogens was demonstrated by their response to known xenoestrogens, and also by the putative identification of two polychlorinated biphenyls (2,3',4, 4,'-tetrachlorobiphenyl and 2,2',3,5',6-pentachlorobiphenyl) as novel estrogenic chemicals. These cell bioassay systems have applications for rapid screening, identification, and characterization of endocrine disrupting chemicals.

Androgens↗
PubMed2003

Induction of an estrogen-responsive reporter gene in rainbow trout hepatoma cells (RTH 149) at 11 or 18 degrees C.

The potential for temperature to influence estrogen-mediated responses in poikilothermic animals suggested that temperature may be an important variable to consider when using an estrogen-responsive reporter gene in a rainbow trout cell line to test chemicals for estrogenic activity. Rainbow trout hepatoma cells (RTH 149) incubated at 11 or 18 degrees C were cotransfected with an estrogen-responsive luciferase reporter plasmid and a plasmid containing a constitutively expressed rainbow trout estrogen receptor. The RTH-149 cells were then exposed to estradiol, with samples collected at 24-h intervals. The 72-h effective concentration for 50% maximal response (EC50) for estrogen-responsive luciferase activity at 11 degrees C was 3.8 x 10(-9) M and 7.4 x 10(-10) M at 18 degrees C. The efficacy of estradiol was lower at 11 degrees C. The maximal response to estradiol in cells at 11 degrees C was generally two- to threefold greater than controls (mean = 2.6-fold), whereas the maximal response at 18 degrees C was three- to fourfold greater than controls (mean = 3.2-fold). Ethinylestradiol, a strong estrogen receptor agonist, was similar to estradiol in potency (relative potency = 0.8) and efficacy at the two temperatures. The EC50 of the weak estrogen receptor agonist 4-tert-pentylphenol was 7.6 x 10(-7) M at 11 degrees C and 6.9 x 10(-7) M at 18 degrees C; its potency relative to 17beta-estradiol was not significantly different at the two temperatures, 0.00036 and 0.00054 at 11 degrees C and 18 degrees C, respectively. The estrogen-responsive reporter gene activity produced by 10(-8) M estradiol was completely inhibited by the two estrogen hormone receptor antagonists, ZM 189,154 and ICI 182,780, at 10(-6) M concentration of either antagonist. Although there may be slight differences in responses between the two temperatures tested here, this assay can be used to effectively determine the relative estrogenic activity of chemicals within the physiological temperature range of rainbow trout.

Animals↗
PubMed2002

Endocrine modulation and the fragile balance of homeostasis--an overview.

Endocrine modulation by natural and synthetic chemicals and the eventually resulting beneficial or adverse effects for human and animal health are controversially debated not only among scientists but particularly in the public. Most information is available on so-called environmental estrogens, however the amount of information on substances interfering with other hormonal axes steadily increases, particularly on those exhibiting (anti)androgenic activities. The aim of this paper is to summarize existing data and to give an overview on the potential pathways leading to interferences of environmental hormones with homeostasis and eventually resulting health effects. Experimental evidence suggests the hypothesis that fetal and neonatal organisms may be at risk if exposed to environmental estrogens. In contrary, it appears as if phytoestrogens, particularly those with selective estrogen receptor modulator- (SERM-)like activities have the potential to be useful in medical application, both as dietary means and as pharmaceuticals. Lacking valid information about the detailed analysis of the molecular mode of action for environmental estrogens, the possibility for an ultimate classification of environmental estrogens in "dangerous endocrine disruptors" and phytoestrogens in "useful pharmaceuticals" cannot be supported conclusively. Nevertheless both activities are likely.

Aging↗
PubMed2002

Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma.

Uterine leiomyomas are the most common gynecologic neoplasm in reproductive-age women. While it is clear that hormonal factors play a prominent role in this disease, how steroid hormones contribute to disease etiology or may be utilized as targets for intervention are currently areas of active scientific investigation. To study the impact of hormones on uterine leiomyomas, the Eker rat has been developed as an in vivolin vitro animal model system for these tumors. Spontaneous leiomyomas arise in intact Eker rats with a high frequency and leiomyoma-derived cell lines from these animals maintain the biochemical and physiological characteristics of the tumors from which they were obtained. Using this animal model system, it has been established that tumor development is absolutely dependent on steroid hormones and that sensitivity/responsiveness to estrogen is enhanced in tumors and tumor-derived cell lines. Modulation of hormonal milieu, such as that which naturally occurs during pregnancy, can effectively inhibit tumor development. The hormone responsiveness of these tumors makes them good candidates for hormonal therapy. Selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene hold promise as potential therapeutic agents for this disease. SERMs inhibit proliferation of leiomyoma-derived cell lines in vitro, repress the growth of these lines in nude mice, and, when administered over a 2- to 4-month course of treatment to Eker rats, reduce tumor incidence by more than 50%. In addition to endogenous hormones, xenoestrogens in our environment (e.g., phytoestrogens, organochlorine pesticides, pharmacologic compounds) are of potential concern with regards to their impact on this disease. These environmental estrogens have been shown to promote the growth of leiomyoma cells in vitro and in vivo. Further elucidation of the role of these and other hormonal and reproductive factors in the development of uterine leiomyoma will be invaluable for increasing our understanding of the etiology of this disease and developing new therapeutic strategies to help to reduce the negative impact of uterine leiomyomas on women's health.

Animals↗
PubMed2003

Role of steroid sulfatase in local formation of estrogen in post-menopausal breast cancer patients.

More than two-thirds of breast cancers occur in post-menopausal women, and depend on the estrogens for their proliferation and survival. For the treatment of estrogen-dependent breast cancers, two major treatment options are now available. One is selective estrogen receptor modulator (SERM) such as Tamoxifen and another is aromatase inhibitor such as Anastrozole, Letrozole and Exemestane, which reduce local in situ formation of estrogens. Although these therapies are clinically active for advanced and early breast cancers, de novo and/or acquired resistance to SERM and/or aromatase inhibitors are also clinical problem. Recent studies suggest that local formation of estrogens in the breast tumors is more important than circulating estrogen in plasma for the growth and survival of estrogen-dependent breast cancer in post-menopausal women. The rationale for the importance of local formation of estrogens is based on the following evidences. Estradiol (E2) levels in breast tumors are equivalent to those of pre-menopausal patients, although plasma E2 levels are 50-fold lower after menopause. E2 concentrations in breast tumors of post-menopausal women are 10-40 times higher than serum level. Biosynthesis of estrogens in breast tumors tissues occurs via two major different routes, one is aromatase pathway and another is steroid-sulfatase (STS) pathway. Whereas many studies has been reported about aromatase inhibitor and its clinical trial results in breast cancer patients, limited information are available regarding to other estrogen regulating enzymes including STS, its role in breast tumors and STS inhibitors. STS is the enzyme that hydrolyses estrone 3-sulfate (E1S) and dehydroepiandrosterone-sulfate (DHEA-S) to their active un-sulfoconjugated forms, thereby stimulating the growth and survival of estrogen-dependent breast tumors. It has been well known that E1S level are much higher than E2 level both in plasma and tumor of post-menopausal patients. Recent reports show that more than 80% of breast tumors are stained with anti-STS antibody and the expression of STS is an independent prognostic factor in breast cancer. Taking these findings into consideration, local formation of estrogens could be partially synthesized from large amount of E1S by STS, which exist in breast cancer. On the other hand, aromatase localizes in stroma and adipocyte surrounding breast cancer. Furthermore, since estrogen formation from E1S and DHEA-S (STS pathway) cannot be blocked by aromatase inhibitors, STS is thought to be a new molecular target for the treatment of estrogen-dependent tumor post-SERM and/or aromatase inhibitors. In this symposium, these recent rationale for the importance of STS in post-menopausal breast cancer patients is reviewed as well as STS inhibitor.

Animals↗
PubMed2003

Characterization and chromosomal instability of novel derived cell lines from a wt-erbB-2 transgenic mouse model.

Amplification and overexpression of the erbB-2 (HER-2/neu) proto-oncogene and exposure to the cell cycle mitogenic hormone estrogen (E2) have been associated with mammary tumorigenesis. Phytoestrogens found in soy act as selective estrogen receptor modulators and may also modify mammary carcinogenesis. We have used the wt-erbB-2 transgenic mouse model to study the effects of estrogen and dietary phytoestrogens on erbB-2-associated mammary tumorigenesis. Transgenic mice were treated with short-term E2 or placebo pellets during the early reproductive period and fed a casein or soy diet for life. Mammary tumors from the different treatment groups were used for the derivation of novel cell lines. Comparative genomic hybridization (CGH), flow cytometry, assays of cell proliferation and soft agar cloning were performed to study genomic instability and in vitro characteristics. CGH data were compared with corresponding parental tumors. Mammary tumors exhibited significantly fewer genetic changes than cell lines by CGH. Cell lines from soy-fed animals (that developed tumors with a longer latency) demonstrated the greatest frequency of chromosomal gain and loss. The E2-treated, casein-fed animals (that developed tumors with the shortest latency) had the fewest genetic changes in derived lines by CGH. Nonetheless, E2-associated tumors in vivo and lines in vitro had the most aggressive phenotypes. In addition, over 40% of all derived cell lines, and both tumors from the placebo-treated casein-fed mice, exhibited loss of chromosome 4 by CGH. In aggregate, our data suggest that estrogenic signaling influences mammary tumor development in this transgenic mouse model bearing the rat wt-erbB-2 gene. Once induced, tumors and derived lines demonstrate persistent phenotypic characteristics, including tumor aggression and shortened latency in E2-treated mice. Loss of chromosome 4 was commonly identified in derived lines and may have facilitated immortalization or passage in culture.

Animals↗
PubMed2001

Acetaminophen elicits anti-estrogenic but not estrogenic responses in the immature mouse.

Acetaminophen is a widely used analgesic, which has exhibited evidence of estrogenic activity in estrogen-receptor positive human breast cancer cells. However, there is limited in vivo experimentation regarding the estrogenicity of acetaminophen. Therefore, the present study examined the in vivo estrogenic potential of acetaminophen using the immature female mouse model. Specifically, C57Bl/6 female mice were treated with acetaminophen (100, 200 and 250 mg/kg per day, i.p.) for 3 consecutive days. Positive controls received estradiol (10 microg/kg per day, i.p.) for 3 consecutive days. Markers of estrogenic activity examined were uterine weight, uterine peroxidase activity and progesterone receptor (PR) up-regulation. The results demonstrated that, at all three doses, acetaminophen did not significantly increase uterine weight, uterine peroxidase activity or PR levels. However, the co-administration of E(2) and acetaminophen (200 mg/kg per day, 3 days, i.p.) resulted in a decrease in the E(2)-induced upregulation of uterine and hepatic nuclear PR (uterine PR values of 39.7+/-6.6 and 23.7+/-3.4 fmol/mg for E(2)+vehicle and E(2)+acetaminophen, respectively, P<0.05). Additionally, the estradiol-induced increase in uterine peroxidase was decreased 75% by acetaminophen (200 mg/kg per day, 3 days, i.p.). Therefore, in the immature mouse model acetaminophen treatment did not elicit estrogenic activity. However, acetaminophen had a limited ability to antagonize the effects of E(2).

Acetaminophen↗
PubMed2003

Challenges in the endocrine management of breast cancer.

The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tamoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tamoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions

Adult↗
PubMed2004

Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques.

In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen replacement, with or without progesterone supplementation for 14 days, significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)-A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1 or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM), raloxifene, have on TPH protein and phosphorylation, and on protein expression of SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but estrogen-like activities in the brain have been reported. Cytoplasmic and membrane extracts of the dorsal raphe region were processed for Western blotting. TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific antibodies. The optical densities of the signals were measured with NIH image and analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and 5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo of estrogen plus progesterone and raloxifene also increased TPH phosphorylation. Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein. However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen alone or combined with progesterone for 1 mo caused a significant reduction in MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene may increase serotonin production and transport. The expression of the degradative enzymes suggests a complex combination of gene transcription, post-transcriptional processing, and substrate feedback mechanisms.

Animals↗
PubMed2003

Estrogen, progesterone and epithelial ovarian cancer.

Ovarian carcinoma (OCa) continues to be the leading cause of death due to gynecologic malignancies and the vast majority of OCa is derived from the ovarian surface epithelium (OSE) and its cystic derivatives. Epidemiological evidence strongly suggests that steroid hormones, primarily estrogens and progesterone, are implicated in ovarian carcinogenesis. However, it has proved difficult to fully understand their mechanisms of action on the tumorigenic process. New convincing data have indicated that estrogens favor neoplastic transformation of the OSE while progesterone offers protection against OCa development. Specifically, estrogens, particularly those present in ovulatory follicles, are both genotoxic and mitogenic to OSE cells. In contrast, pregnancy-equivalent levels progesterone are highly effective as apoptosis inducers for OSE and OCa cells. In this regard, high-dose progestin may exert an exfoliation effect and rid an aged OSE of pre-malignant cells. A limited number of clinical studies has demonstrated efficacies of antiestrogens, aromatase inhibitors, and progestins alone or in combination with chemotherapeutic drugs in the treatment of OCa. As a result of increased life expectancy in most countries, the number of women taking hormone replacement therapies (HRT) continues to grow. Thus, knowledge of the mechanism of action of steroid hormones on the OSE and OCa is of paramount significance to HRT risk assessment and to the development of novel therapies for the prevention and treatment of OCa.

Animals↗
PubMed2005

The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer.

Effective treatment of estrogen receptor (ER)-positive breast cancers with tamoxifen is often curtailed by the development of drug resistance. Antiestrogen-resistant breast cancers often show increased expression of the epidermal growth factor receptor family members, ErbB1 and ErbB2. Tamoxifen activates the cyclin-dependent kinase inhibitor, p27 to mediate G(1) arrest. ErbB2 or ErbB1 overexpression can abrogate tamoxifen sensitivity in breast cancer lines through both reduction in p27 levels and inhibition of its function. Here we show that the dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), can restore tamoxifen sensitivity in ER-positive, tamoxifen-resistant breast cancer models. Treatment of MCF-7(pr), T-47D, and ZR-75 cells with lapatinib or tamoxifen alone caused an incomplete cell cycle arrest. Treatment with both drugs led to a more rapid and profound cell cycle arrest in all three lines. Mitogen-activated protein kinase and protein kinase B were inhibited by lapatinib. The two drugs together caused a greater reduction of cyclin D1 and a greater p27 increase and cyclin E-cdk2 inhibition than observed with either drug alone. In addition to inhibiting mitogenic signaling and cell cycle progression, lapatinib inhibited estrogen-stimulated ER transcriptional activity and cooperated with tamoxifen to further reduce ER-dependent transcription. Lapatinib in combination with tamoxifen effectively inhibited the growth of tamoxifen-resistant ErbB2 overexpressing MCF-7 mammary tumor xenografts. These data provide strong preclinical data to support clinical trials of ErbB1/ErbB2 inhibitors in combination with tamoxifen in the treatment of human breast cancer.

Breast Neoplasms↗
PubMed2005

Gene expression profiling of breast cancer in relation to estrogen receptor status and estrogen-metabolizing enzymes: clinical implications.

Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER- and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expression of the ER in all cases, leading to the recognition of several further subclasses of tumors. When the tumor classes obtained by whole genome gene expression analysis were compared with those obtained by independent quantitation of the estradiol-metabolizing enzymes, a statistically significant association between both classification groups was observed. These findings point to a possible association between development of a tumor with a particular expression profile and its capacity to synthesize estradiol as measured by the expression of the transcripts for the necessary key enzymes. Further, whole genome expression patterns were studied in 12 patients treated with anastrozole. Using significance analysis of microarrays, we identified 298 genes significantly differently expressed between partial response and progressive disease groups.

Breast Neoplasms↗
PubMed2005

The Vitamin D endocrine system of the gut--its possible role in colorectal cancer prevention.

While Vitamin D insufficiency in the US and European population is rising, epidemiological studies suggest an inverse correlation between low serum levels of 25-hydroxyvitamin D(3) (25-OH-D(3)) and colorectal cancer incidence. The antimitotic, prodifferentiating and proapoptotic active metabolite 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)-D(3)) is synthesized also by colonocytes, since these possess Vitamin D synthesizing (CYP27B1) and catabolic (CYP24) hydroxylases similar to the kidney. Early during colon tumor progression, expression of CYP27B1 and of the Vitamin D receptor increases, suggesting an autocrine/paracrine growth control in colon tissue as a physiological restriction against tumor progression. However, in human adenocarcinomas expression of the catabolic CYP24 is also enhanced when compared with adjacent normal mucosa. Therefore, to maintain colonic accumulation of 1,25-(OH)(2)-D(3) its catabolism needs to be restricted. Our studies in mice show that low nutritional calcium causes hyperproliferation of colon crypts and significant elevation of CYP24 expression, which can be completely abrogated by soy feeding. We suggest that phytoestrogens in soy, known to be estrogen receptor modulators, are responsible for decreased CYP24 expression. These results and our observation that 17beta-estradiol can elevate CYP27B1 expression in rectal tissue of postmenopausal women, may underlie the observed protective effect of estrogens against colorectal cancer in females.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2004

Design, synthesis, and evaluation of peptides with estrogen-like activity.

Currently used antiestrogenic drugs against hormone-dependent breast cancer, and estrogenic drugs used in treatment of osteoporosis, are associated with risk factors. Therefore, there is a strong need to develop selective estrogen receptor modulators with better tissue selectivity. In a recent study (Peptides, 2002, Vol. 3, 573-580), we used a monoclonal antibody to estradiol (mAb-E2) to screen a phage-display peptide library. We identified a 15-mer peptide (peptide H5) that recognizes mAb-E2 (IC(50) 1 microM) and estrogen receptor (ER)alpha (IC(50) 500 microM) but not ERbeta, and displays estrogen-like activity in vitro and in vivo. In this study, we designed and prepared peptides based on peptide H5, which possess improved estrogenic activity, by evaluating their binding to mAb-E2 and to ERs. Initially, we determined the minimal binding sequence of peptide H5 capable of binding mAb-E2 and ER. Subsequently, systematic single-residue replacements of the minimal sequence, followed by multiple-residue replacements, yielded hexa- and heptapeptides with increased affinities to mAb-E2 and to ER. The most promising peptides, VSWFFE (EMP-1) and VSWFFED (EMP-2) (EMP: estrogen-mimetic peptide), bind mAb-E2 with high affinity (IC(50) of 6 and 30 nM, respectively), recognize ERs with increased affinity (IC(50) of 100 microM for ERalpha, and 100-250 microM for ERbeta), and possess estrogenic activity in vivo. The short peptides described in this study may be used as potential lead compounds for developing new ER ligands.

Alanine↗