Estrogen-dependent Tumors Research Articles

Low Dose Estrogen Supplementation Reduces Mortality of Mice in Estrogen-Dependent Human Tumor Xenograft Model

Breast cancer is one of the most frequent female cancers in the Western world. Perturbation of estrogen levels by hormone replacement therapy or pregnancy is associated with a variety of diseases, including breast cancer. Estrogen supplementation is required to establish appropriate animal models for estrogen-related diseases. In this report, we demonstrated that supplementation with high doses of 17beta-estradiol results in deaths in estrogen-dependent MCF-7 tumor xenograft model. Renal damage and bladder stone formation was implicated as a major cause of death. The mortality rate was significantly reduced when mice received a low dose of 17beta-estradiol. We also confirmed that low dose of 17beta-estradiol supplementation can support the growth of tumors in MCF-7 tumor xenograft model. These results suggest that low dose estrogen supplementation may be more appropriate in estrogen-dependent tumor xenograft models.

Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists

This was a preliminary study to determine the effect of aromatase inhibitors in preventing the flare induced by GnRH agonist (GnRH-a) in women with endometriosis (n = 9) or leiomyomata (n = 4) who were given letrozole on the first 5 days of the GnRH-a therapy. Serum LH and FSH levels showed the typical flare 1 day after the injection of the GnRH-a; however, E(2) declined immediately after letrozole administration and was notably suppressed at 1, 2, and 4 days after GnRH-a. No patients complained of clinical symptoms typical of the GnRH-a flare phenomenon.

Phytoestrogens and breast cancer: a complex story

Genistein is an isoflavone with oestrogenic activity that is present in a variety of soy products as a constituent of complex mixtures of bioactive compounds, whose matrix profiles play an important role in determining the overall oestrogenic bioactivity of genistein. We review data on how the profile of soy bioactive compounds can modulate genistein-stimulated oestrogen-dependent tumour growth. Our research has focused on the effects of dietary genistein on the growth of oestrogen (E)-dependent mammary tumours both in vitro and in vivo. Genistein enhances the proliferation of E-dependent human breast cancer tumour growth. In a similar manner, dietary genistein stimulates tumour growth in the chemically-induced (NMU) mammary cancer rodent model. Genistin, the glycoside of genistein, simulates growth similar to that of genistein and withdrawal of either genistein or genistin results in tumour regression. The extent of soy processing modulates the effects of dietary genistein in vivo as soy protein isolate, a highly purified and widely used source of protein that is processed to contain low, medium, and high amounts of isoflavones, stimulate the growth of the E-dependent mammary tumours in a dose dependent manner. In contrast to the more purified diets, studies with soy flour of equivalent genistein levels did not stimulate the growth of E-dependent breast cancer tumours in vivo. However, the size of these tumours also did not regress as is observed in control groups in which oestrogen and genistein have been withdrawn. The expression of the oestrogen-target genes of pS2, progesterone receptor, and cyclin D1 correlates with the growth of E-dependent tumours and has been consistently observed to be induced in response to treatment with dietary genistein. To evaluate whether dietary genistein interacts with current anti-oestrogen breast cancer therapies such as tamoxifen (TAM), we implanted E-dependent tumours into ovariectomized athymic mice and administered oestradiol, oestradiol plus TAM, or oestradiol, TAM, and dietary genistein. In these studies dietary genistein was able to negate the inhibitory effect of TAM on E-stimulated tumour growth. In summary, genistein can act as an oestrogen agonist resulting in proliferation of E-dependent human breast cancer tumours in vivo and its activity can be modulated by the presence of other bioactive components in complex soy foods. Additionally, dietary genistein can negate the inhibitory effects of TAM on E-stimulated growth of MCF-7 cell tumours implanted into ovariectomized athymic mice.

Efeitos da melatonina no sistema genital feminino: breve revisão

Melatonin is secreted by the pineal gland and this is linked to the day/night cycle. It is an antioxidant and plays a fundamental role in the regulation of the jet-lag stage, in several physiological reactions and in control of the biologic rhythm. Human melatonin has an important influence on the female genital system. In fact, melatonin may influence production and action of steroids, modifying cellular signalization on the target tissue. There are many evidences that the melatonin therapy may be interfering with neoplasia development, mainly of the estrogen-dependent tumor. This paper aims to analyze the actions of melatonin on the neuroendocrine, immunological and cardiovascular systems, as well as on the reproductive function.

Melatonin down-regulates hTERT expression induced by either natural estrogens (17β-estradiol) or metalloestrogens (cadmium) in MCF-7 human breast cancer cells

The goal was to evaluate whether melatonin (Mel) down-regulates hTERT expression induced by 17β-estradiol (E 2) or cadmium (Cd) in breast cancer cells. We found that: (a) Mel inhibits E 2 or Cd-induced hTERT transcription in hTERT-Luc transfected MCF-7 cells, (b) Mel significantly reduces E 2- and Cd-mediated hTERT transactivation triggered by ERα in transfected HeLa cells, (c) Mel inhibits hTERT expression induced by E 2 or Cd in MCF-7 cells. Melatonin inhibition of telomerase activity supports a possible role in treatment of estrogen-dependent tumors or carcinogenesis by environmental or occupational exposure to xenoestrogens.

Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model

Although the aromatase inhibitor anastrozole has been shown to be very effective in the treatment of hormone-dependent postmenopausal breast cancer, some patients with advanced disease will develop resistance to treatment. To investigate therapeutic strategies to overcome resistance to anastrozole treatment, we have used an intratumoral aromatase model that simulates postmenopausal breast cancer patients with estrogen-dependent tumors. Growth of the tumors in the mice was inhibited by both anastrozole and fulvestrant compared with the control tumors. Nevertheless, tumors had doubled in size at 5 weeks of treatment. We therefore investigated whether switching the original treatments to anastrozole or fulvestrant alone or the combination of anastrozole plus fulvestrant would reduce tumor growth. The results showed that the best strategy to reverse the insensitivity to anastrozole or fulvestrant is to combine the two agents. Additionally, the tumors treated with anastrozole plus fulvestrant from the beginning had only just doubled their size after 14 weeks of treatment, whereas the anastrozole and fulvestrant treatments alone resulted in 9- and 12-fold increases in tumor size, respectively, in the same time period. Anastrozole plus fulvestrant from the beginning or in sequence was associated with down-regulation of signaling proteins involved in the development of hormonal resistance such as insulin-like growth factor type I receptor beta, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor alpha compared with tumors treated with anastrozole or fulvestrant alone. These results suggest that blocking the estrogen receptor and aromatase may delay or reverse the development of resistance to aromatase inhibitors in advanced breast cancer patients.

Modelling estrogen receptor alpha-positive breast cancer by transformation of normal human mammary epithelial cells

Two-thirds of breast cancers express estrogen receptor alpha (ERα) and are estrogen-dependent for growth, yet the unavailability of accurate in vivo models has long impeded the characterisation of critical events that lead to the development of these luminal subtypes of the disease. Previously, our group successfully created an ERα-positive breast cancer model by quantitative transformation of normal human mammary epithelial cells (HMECs) derived from reduction mammoplasties. HMECs were grown as mammospheres in suspension to enrich for progenitor cells, which were then transformed using lentiviral vectors encoding ERα and TERT as well as the polycomb gene BMI1 and MYC, both of which have been implicated in ERα-positive breast cancer. Injection of transformed HMECs into mammary fad pads of NOD/SCID mice resulted in the formation of estrogen-dependent tumours that metastasised to multiple organs [1], confirming the creation of a model that mirrors the characteristics of human estrogen-dependent breast cancer. Somewhat surprisingly, we observed islands of squamous differentiation in the tumours that formed in the NOD/SCID mice, whereas the large majority of human breast tumours are adenocarcinomas. To address this discrepancy, we are currently testing a combination of our established protocol with new HMECs in vitro culture conditions that have recently been shown to abrogate the squamous phenotype of the resulting tumours in mice [2]. Our model system is a powerful tool for the in vivo characterisation of candidate genes that have been implicated in development of ERα-positive breast cancer. Genes of interest include TNRC9, which has recently been identified in genome-wide association studies as a potential novel breast cancer susceptibility gene [3], as well as TBX3, which is known to play a role in mammary gland development as well as breast tumourigenesis. We are currently testing these genes in our model using overexpression and knockdown approaches.

Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells

Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on oestrogen-dependent tumours. Recently, it has been described that melatonin, on the basis of its antioxidant properties, inhibits the growth of glioma cells. Glioma cells express oestrogen receptors and have the ability to synthesise oestrogens from androgens. In the present study, we demonstrate that pharmacological concentrations of melatonin decreases the growth of C6 glioma cells and reduces the local biosynthesis of oestrogens, through the inhibition of aromatase, the enzyme that catalyses the conversion of androgens into oestrogens. These results are supported by three types of evidence. Firstly, melatonin counteracts the growth stimulatory effects of testosterone on glioma cells, which is dependent on the local synthesis of oestrogens from testosterone. Secondly, we found that melatonin reduces the aromatase activity of C6 cells, measured by the tritiated water release assay. Finally, by (RT)–PCR, we found that melatonin downregulates aromatase mRNA steady-state levels in these glioma cells. We conclude that melatonin inhibits the local production of oestrogens decreasing aromatase activity and expression. By analogy to the implications of aromatase in other forms of oestrogen-sensitive tumours, it is conceivable that the modulation of the aromatase by pharmacological melatonin may play a role in the growth of glioblastomas.

Dietary Flaxseed Interaction With Tamoxifen Induced Tumor Regression in Athymic Mice With MCF-7 Xenografts by Downregulating the Expression of Estrogen Related Gene Products and Signal Transduction Pathways

Our previous short-term study has shown that 10% flaxseed (FS) inhibits the growth of human estrogen dependent estrogen receptor positive breast tumors (MCF-7) xenografts in ovariectomized (OVX) athymic mice and enhances the tumor inhibitory effect of tamoxifen (TAM). This study determined the long-term effect of 5% and 10% FS, with or without TAM, on the growth of MCF-7 xenografts in athymic mice and the potential mechanisms of actions. OVX mice with established MCF-7 tumors were treated with basal diet (control), 5% FS (5FS), 10% FS (10FS), and TAM (5 mg/pellet, 60-day release), alone or in combination, for 16 wk without estrogen supplementation. Tumor growth was monitored weekly. At sacrifice, the tumors were analyzed by immunohistochemistry for cell proliferation, apoptosis, and expression of estrogen-related genes and signal transduction pathways. Both 5FS and 10FS regressed the pretreatment tumor size by over 90% similar to control. TAM initially regressed the tumors but then induced a regrowth; thus, only a final 6% reduction from pretreatment tumor size was achieved, which was attenuated by combining TAM with 10FS but not with 5FS. TAM combined with 10FS regressed tumors to 55% of pretreatment tumor size due to decreased cell proliferation and increased apoptosis. The expressions of cyclin D1, estrogen receptor α, human epidermal growth factor receptor 2, and insulin-like growth factor I receptor in the TAM group were significantly reduced when TAM was combined with 5FS or 10FS. In conclusion, after long-term treatment, FS did not stimulate tumor growth and combined with TAM, regressed tumor size in part due to downregulation of the expression of estrogen-related gene products and signal transduction pathways.

Analysis of adjuvant endocrine therapy on the prognosis of endometrial carcinoma confined to the uterus

Endometrial carcinoma is an estrogen-dependent tumor. It has been generally accepted that progesterone is effective in women with advanced and/or recurrent endometrial carcinoma and that it should be considered in young patients with early stage disease who desire to preserve their fertility. However whether adjuvant endocrine therapy should be performed routinely after surgery especially in patients whose tumor is confined to the uterus is subject to debate. The aim of the present study was to observe the effects of adjuvant endocrine therapy on the prognosis of patients with stage I/II endometrial carcinoma. A retrospective study was carried out from 1992 to 2004 with 168 women admitted to Peking University Peoples Hospital with endometrial carcinomas confined to the uterus. The 60 women who accepted to undergo endocrine therapy for more than 12 months following surgery formed the endocrine therapy group (the mean ± SD therapy duration was 18.2 ± 9.6 months) and the other 108 women served as controls. The study patients received a daily oral dose of 250 mg of medroxyprogesterone acetate (Peking Creative Fortune Pharmaceutical Peking China). The clinical and pathologic characteristics did not differ much between the 2 groups. (excerpt)

Estrogen-Induced Generation of Reactive Oxygen and Nitrogen Species, Gene Damage, and Estrogen-Dependent Cancers

In addition to the direct effect of estrogen on mitochondria and the redox cycling of catechol estrogen, estrogen-induced proinflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), also generate reactive oxygen and nitrogen species (RO/NS). Different cellular signaling pathways may operate in response to varying levels of estrogen-induced RO/NS, leading to genotoxic damage, cell apoptosis, or cell growth. At high levels of RO/NS, cells receiving genotoxic insults, if not repaired, may engage the apoptotic pathways. There is increasing evidence supporting that estrogen-induced alterations in the genome of cells is produced by oxidative attack. Furthermore, ROS generated by estrogen exposure and/or active metabolites of estrogen in combination with receptor-mediated proliferation of genetically damaged cells may be involved in tumor development. This view is supported by the findings of DNA modifications produced in vitro or in vivo by natural and synthetic estrogens in the target organs of cancer both in experimental models and in humans. Interaction of estrogen-induced oxidants and estrogen metabolites with DNA was shown to generate mutations in genes. Cotreatment with an inhibitor of IL-1β and TNF-α synthesis, pentoxifylline, decreased stilbene estrogen-induced levels of myeloperoxidase (MPO), 8-hydroxydeoxyguanosine formation, and gene mutations, and prevented stilbene estrogen-induced lesions. Stable MCF-7 clones overexpressing IL-1β resulted in a high level of IL-1β peptide secretion undergoing cell apoptosis, and an elevated level of p53 protein in response to high oxidative stress when compared to nontransfected cells, whereas MCF-7 clones overexpressing IL-1β that resulted in a moderate level of IL-1β secretion stimulated the clonal expansion of MCF-7 and TM3 cells. Estrogen-induced MCF-7 cell growth and cyclin D1 expression were suppressed by antioxidants and mitochondrial blockers. These studies support that in addition to ovarian estrogen-mediated ER signaling, mitogenic signals may also come from estrogen-induced RO/NS. Further validation of this concept that the concentration of the RO/NS within the cellular microenvironment determines its stimulatory or inhibitory growth signals as well as its genotoxic effects regulating the growth of estrogen-dependent tumors may result in novel preventive strategies.

Synthesis and Preliminary Biological Evaluation of Estrone Dimers

A rapid and efficient synthesis of estrogenic dimers, with 45% overall yield, is described. The new molecules possess two estrone units linked at position 16, with either an alkyl chain or a polyethylene glycol chain. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent human breast tumor cell lines: MCF-7 and MDA-MB-231.

Benigne Brusterkrankungen - Ätiologie und Klinik

Der Begriff der benignen Brusterkrankung umfasst eine sehr heterogene Gruppe von Veränderungen des Brustgewebes. Bei der Betrachtung benigner Brustveränderungen ist besondere Aufmerksamkeit zu richten auf eine exakte Diagnosefindung, die Abgrenzung zu invasiven Läsionen und die Durchführung einer adäquaten Therapie. Da einige benigne Veränderungen nur ungenau definiert sind, ist eine exakte Diagnose zuweilen schwierig. Diese ist jedoch unerlässlich hinsichtlich des einigen benignen Brusterkrankungen zugrunde liegenden relativen Mammakarzinomrisikos. Benigne Läsionen der Brust können als Mamillensekretion, Mastodynie und palpabler Tumor in Erscheinung treten oder als Zufallsbefund in der Mammografie oder Biopsie diagnostiziert werden. Benigne Brusterkrankungen erscheinen als hormonabhängige Veränderungen des Brustgewebes. Die östrogeninduzierte Zellproliferation ist ein entscheidender Schritt in der Karzinogenese von Malignomen der Mamma. Studien haben eine im Vergleich zum benignen Brustgewebe erniedrigte ERβ-Expression in Karzinomen gezeigt. Der Verlust der ERβ-Expression ist möglicherweise eine der bedeutenden Zwischenstufen in der Entstehung östrogenabhängiger Tumoren. In dieser Übersicht wird der aktuelle Kenntnisstand zu benignen Brusterkrankungen unter besonderer Berücksichtigung ihrer Ätiologie und Klinik zusammengefasst.

Estrogen-Induced Activation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor Expression, and Edema in the Uterus Are Mediated by the Phosphatidylinositol 3-Kinase/Akt Pathway

Vascular endothelial growth factor (VEGF) plays an essential role in normal uterine physiology and function as well as endometrial cancer and other uterine disorders. Recently we showed that estrogen regulation of VEGF expression in the rat uterus involves rapid recruitment of both estrogen receptor (ER)-alpha and hypoxia-inducible factor (HIF)-1alpha to the VEGF promoter. Estrogen is known to stimulate both the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways, which have been linked to the activation of both of these transcription factors. Therefore, the involvement of these pathways in estrogen-induced VEGF expression was investigated. Inhibitors of the MAPK (U0126) or PI3K pathways (wortmannin or LY294002) were administered ip to immature female rats 1 h before 17beta-estradiol (E(2)) treatment. E(2) activation of both pathways occurred and was completely inhibited by the appropriate antagonist. Only PI3K inhibitors, however, blocked E(2) stimulation of VEGF mRNA expression and E(2)-induced uterine edema. In vivo chromatin immunoprecipitation analysis showed that this was associated with a failure of both HIF-1alpha and ERalpha to bind to the VEGF promoter. To determine whether inhibiting the PI3K pathway affected ERalpha induction of other estrogen target genes, the expression of creatine kinase B and progesterone receptor A/B was also examined. The expression of each was also inhibited by wortmannin, as was ERalpha binding to the creatine kinase B promoter. In conclusion, although estrogen activates both the MAPK and PI3K pathways in the rat uterus, activation of HIF-1alpha and ERalpha, and therefore regulation of VEGF gene expression is dependent only on the PI3K/Akt pathway. Furthermore, activation of the PI3K pathway appears to be a common requirement for the expression of estrogen-induced genes. These findings not only shed light on estrogen action in normal target tissues but also have important implications for cancer biology because excessive PI3K, HIF-1alpha, and VEGF activity are common in estrogen-dependent tumors.

Estrogen sulfotransferase expression in endometrial stromal sarcomas: An immunohistochemical study

Levels and activity of the enzyme estrogen sulfotransferase (EST) have been reported to play an important role in the regulation of in situ estrogen levels in human breast, prostate, and endometrial cancer. To better understand growth progression in endometrial stromal sarcomas (ESS), estrogen-dependent tumors, we analyzed the expression of EST in a series of 29 ESS. Archival formalin-fixed, paraffin-embedded material was analyzed immunohistochemically with a monoclonal antibody to EST using the peroxidase–antiperoxidase method. A score was calculated based on the percentage of positive tumor cells and staining intensity. EST staining was identified in 5 of 29 (18%) ESS and was scored as weakly positive, while 24 of 29 (82%) ESS were negative for EST. We demonstrate that a subset of ESS express EST, which may allow them to inactivate intratumoral estrogens. ESS without EST expression may have increased levels of biologically active estrogen, which explains the tumor progression of this entity and these patients may be at increased risk for recurrences and metastases.

Antiestrogenic Glyceollins Suppress Human Breast and Ovarian Carcinoma Tumorigenesis

We have identified the phytoalexin compounds glyceollins I, II, and III, which exhibit marked antiestrogenic effects on estrogen receptor function and estrogen-dependent tumor growth in vivo. The purpose of this study was to investigate the interactions among the induced soy phytoalexins glyceollins I, II, and III on the growth of estrogen-dependent MCF-7 breast cancer and BG-1 ovarian cancer cells implanted in ovariectomized athymic mice. Four treatment groups for each cell line were used: vehicle control, 20 mg/kg/mouse/d glyceollin mixture injection, 0.72 mg estradiol (E2) implant, and E2 implant + 20 mg/kg/mouse/d glyceollin injection. Treatment with glyceollin suppressed E2-stimulated tumor growth of MCF-7 cells (-53.4%) and BG-1 cells (-73.1%) in ovariectomized athymic mice. These tumor-inhibiting effects corresponded with significantly lower E2-induced progesterone receptor expression in the tumors. In contrast to tamoxifen, the glyceollins had no estrogen-agonist effects on uterine morphology and partially antagonized the uterotropic effects of estrogen. These findings identify glyceollins as antiestrogenic agents that may be useful in the prevention or treatment of breast and ovarian carcinoma.

Aromatase Inhibitors and Bone Health in Women With Breast Cancer

The role of aromatase (estrogen synthetase) inhibitors (AIs) in breast cancer has expanded since their introduction in the mid-1990s. They are superior to tamoxifen in the treatment of postmenopausal women with estrogen-dependent tumors in the metastatic, neoadjuvant, and adjuvant settings. The profound estrogen depletion with AIs is responsible for improved antitumor effect but has led to concerns about healthy organs such as bone. This is particularly important in postmenopausal patients already at risk of osteoporosis and bone fracture because of premature menopause and toxic effects from chemotherapy and steroids. Compounding this, 80% of metastases develop in bone, which increase the risk of fracture through osteoclast-mediated destruction of surrounding bone. The American Society of Clinical Oncology (ASCO) currently recommends an AI as adjuvant therapy in postmenopausal women with hormone receptor–positive early breast cancer, either as initial monotherapy or after tamoxifen therapy. Trials examining their use beyond 5 years and their role as preventatives in healthy women are underway. Therefore, it is imperative that oncologists are familiar with long-term toxicities associated with AI therapy. This review summarizes emerging preclinical and clinical data related to the effects of AIs on bone mineral density, markers of bone turnover, and clinical fracture rates, and offers surveillance and clinical management recommendations with respect to bone health in women receiving chronic AI therapy.

Evidence that corticotropin-releasing hormone inhibits cell growth of human breast cancer cells via the activation of CRH-R1 receptor subtype

It has been previously shown that corticotropin-releasing hormone (CRH) exerts antiproliferative activity on an estrogen-dependent tumor cell line, i.e. human endometrial adenocarcinoma Ishikawa (IK) cells. Here we have investigated the effects of CRH on another estrogen-dependent tumor cell line, human breast cancer MCF7 cells. In this paradigm, CRH given at a fixed concentration of 100 nM significantly inhibited cell growth induced by 100 nM estradiol (E2) after 48 and 72 h of incubation. This effect was not associated with the induction of apoptosis. CRH inhibition of cell proliferation was counteracted in a concentration-dependent manner by the non-selective CRH receptor antagonist, astressin, as well as by a CRH-R1 selective receptor antagonist, antalarmin. RNase protection assays carried out on MCF7 under basal conditions showed that these cells express in a constitutive manner the CRH-R1 receptor subtype. We have also investigated the putative source of CRH acting on breast cancer cells; we found that MCF7 cells express CRH mRNA under basal conditions and secrete sizable amounts of immunoreactive CRH, which leads to postulate the existence of paracrine–autocrine inhibitory mechanism operated by CRH in breast cancer cells.

Synthesis of unique 17β-estradiol homo-dimers, estrogen receptors binding affinity evaluation and cytocidal activity on breast, intestinal and skin cancer cell lines

A rapid and efficient synthesis of a series of C 2-symmetric 17β-estradiol homo-dimers is described. The new molecules are linked at position 17α of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in only five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER + and ER −) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER + cell line. However, they are not very cytotoxic when compared to the antiestrogen tamoxifen. Unfortunately, they show only weak affinity for the estrogen receptor alpha (ERα) and no affinity for the estrogen receptor beta (ERβ). The new compounds were also tested on human intestinal (HT-29) cancer and on murine skin cancer (B16-F10) cell lines for further biological assessment. Interestingly, the dimers were found to be cytotoxic to the murine skin cancer cell line but were inactive towards the intestinal cancer cell line.

Human Hydroxysteroid (17-β) Dehydrogenase 1 Expression Enhances Estrogen Sensitivity of MCF-7 Breast Cancer Cell Xenografts

Hydroxysteroid (17-beta) dehydrogenase 1 (HSD17B1) catalyzes the conversion between estrone (E1) and estradiol (E2). The reaction is reversible in vitro, but the data in cultured cells suggest that E2 production is the predominant reaction in physiological conditions. However, the hypothesis has not been verified in vivo. In the present study, estrogen-dependent MCF-7 human breast cancer cells were stably transfected with an expression plasmid for human HSD17B1. The enzyme efficiently converted E1 to E2 and enhanced the estrogen-dependent growth of cultured MCF-7 cells in the presence of hormonally less active E1. The HSD17B1-expressing cells also formed estrogen-dependent tumors in immunodeficient nude mice. After treating the mice with an appropriate dose of the substrate (E1, 0.1 micromol/kg x d), a marked difference in tumor growth was observed between nontransfected and HSD17B1-transfected MCF-7 cells, mean tumor weights at the end of E1 treatment being 23.2 and 130.4 mg, respectively. Furthermore, estrogen-dependent growth of the HSD17B1-expressing xenografts in the presence of E1 was markedly inhibited by administering 5 micromol/kg x d of a specific HSD17B1 inhibitor. After a 4-wk treatment, the tumor size was reduced by 59.8% as compared with the nontreated tumors, whereas the uterine growth of the mice was not affected by the HSD17B1 inhibitor used. This was in line with the induction of apoptosis of the tumors. The results evidently show that estrogenic response for E1 is enhanced by the local action of HSD17B1 in vivo, and thus, the enzyme is a potential target for pharmacological inhibition of estrogen action.