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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogens play an important role in breast cancer development. Aromatase (CYP19), a cytochrome P450, is the enzyme that synthesizes estrogens. Aromatase is expressed at a higher level in human breast cancer tissue than in normal breast tissue using enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture, animal experiments using aromatase-transfected breast cancer cells, and transgenic mouse studies have demonstrated that in situ produced estrogen plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase has been shown to stimulate breast cancer growth in both an autocrine and a paracrine manner. RT-PCR and gene transcriptional studies have revealed that aromatase promoter switches from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancereous tissue. Suppression of in situ estrogen biosynthesis can be achieved by the prevention of aromatase expression or by the inhibition of aromatase activity in breast tumors. While the control mechanism of aromatase expression in breast cancer tissue is not yet fully understood, aromatase-inhibitor therapy is considered for second-line treatment in patients who fail anti-estrogen therapy. Twenty to thirty percent of the patients who fail anti-estrogen treatment respond to aromatase-inhibitor treatment. Several potent and selective aromatase inhibitors have been developed and used to treat breast cancer. The binding nature of various aromatase inhibitors has been examined by computer modeling, site-directed mutagenesis of aromatase, and inhibition kinetics. The enzyme structure-function studies have led to the development of a computer model of the active site region of human aromatase. The model is used to evaluate the interaction of phytoestrogens such as flavones and isoflavones with aromatase. The study provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones. The phytoestrogen studies will help to determine which fruits and vegetables (those containing the appropriate phytoestrogens) should be included in the diet of postmenopausal women in order to reduce the incidence for breast cancer by inhibiting estrogen biosynthesis in breast tissue.
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PMID:Aromatase and breast cancer. 969 81

Estrogens are important for both normal cell growth and malignant proliferation in the mammary gland as well as in the endometrium. Tamoxifen is a non-steroidal anti-estrogen widely used in breast cancer treatment. In recent years reports have been made of an increased risk of endometrial carcinoma during tamoxifen treatment. We used surgically menopausal cynomolgus macaques to study proliferation and p53 expression during hormonal replacement therapy (HRT) and tamoxifen treatment. Animals were treated continuously for 35 months with either conjugated equine estrogens (CEE; n = 20); medroxyprogesterone acetate (MPA; n = 17); the combination of CEE + MPA (n = 13); or tamoxifen (n = 17) for 35 months. We found an increased expression of p53 in normal breast and endometrial tissue linked to CEE but not tamoxifen treatment. In the breast alveoli there was an association between proliferation measured by morphometry and p53 expression in all groups. However, in the endometrium CEE induced significantly more p53 positivity than tamoxifen, 9/20 vs. 3/17 in glands and 9/19 vs. 0/17 in stroma, respectively. If indeed long-term treatment with tamoxifen as in the present study could inactivate the tumor-suppressive function of p53, endometrial cells might thereby become more susceptible to genetic lesions associated with carcinogenesis.
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PMID:p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques. 1020 73

Estrogens have important functions in mammary gland development and carcinogenesis. To better define these roles, we have used two previously characterized lines of genetically altered mice: estrogen receptor-alpha (ER alpha) knockout (ERKO) mice, which lack the gene encoding ER alpha, and mouse mammary virus tumor (MMTV)-Wnt-1 transgenic mice (Wnt-1 TG), which develop mammary hyperplasia and neoplasia due to ectopic production of the Wnt-1 secretory glycoprotein. We have crossed these lines to ascertain the effects of ER alpha deficiency on mammary gland development and carcinogenesis in mice expressing the Wnt-1 transgene. Introduction of the Wnt-1 transgene into the ERKO background stimulates proliferation of alveolar-like epithelium, indicating that Wnt-1 protein can promote mitogenesis in the absence of an ER alpha-mediated response. The hyperplastic glandular tissue remains confined to the nipple region, implying that the requirement for ER alpha in ductal expansion is not overcome by ectopic Wnt-1. Tumors were detected in virgin ERKO females expressing the Wnt-1 transgene at an average age (48 weeks) that is twice that seen in virgin Wnt-1 TG mice (24 weeks) competent to produce ER alpha. Prepubertal ovariectomy of Wnt-1 TG mice also extended tumor latency to 42 weeks. However, pregnancy did not appear to accelerate the appearance of tumors in Wnt-1 TG mice, and tumor growth rates were not measurably affected by late ovariectomy. Small hyperplastic mammary glands were observed in Wnt-1 TG males, regardless of ER alpha gene status; the glands were similar in appearance to those found in ERKO/Wnt-1 TG females. Mammary tumors also occurred in Wnt-1 TG males; latency tended to be longer in the heterozygous ER alpha and ERKO males (86 to 100 weeks) than in wild-type ER alpha mice (ca. 75 weeks). We conclude that ectopic expression of the Wnt-1 proto-oncogene can induce mammary hyperplasia and tumorigenesis in the absence of ER alpha in female and male mice. The delayed time of tumor appearance may depend on the number of cells at risk of secondary events in the hyperplastic glands, on the carcinogenesis-promoting effects of ER alpha signaling, or on both.
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PMID:A mouse mammary tumor virus-Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha. 1021 94

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)
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PMID:EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. 1041 81

Estrogens play an important role in the development and progression of breast cancer. Although estrogen antagonist treatment often results in the arrest or remission of breast cancer growth, most breast cancers recur and become resistant to estrogen ablative therapy. The molecular mechanisms underlying these actions remain largely undefined. It is hypothesized that tumor cells of an advanced stage may develop compensatory pathways to stimulate the expression of estrogen receptor (ER) target genes or downstream events, independent of estrogen action. In this study, we developed a chimeric repressor to turn off ER target genes with the aim of directly investigating the role of ER target genes in tumor progression. The chimeric repressor contains the ER DNA-binding domain that recognizes estrogen response elements (EREs), a Krupple-associated box (KRAB) repressor domain which silences target genes when tethered to their promoter regions and a truncated progesterone ligand-binding domain which responds only to the exogenous synthetic ligand, RU486. The ability of the chimeric repressor to block ER mediated transcription was assessed in transient transfection assays. ER-induced reporter activity was inhibited by the repressor in a dose-dependent manner, with the maximum effect of more than 80% reduction. The inhibitory activity of the chimeric repressor was tightly under the control of RU486. Effective suppression by the repressor on the natural promoter of ER target gene, complement factor 3 (C3), was also observed. The inhibitory activity was specific to ER, since the repressor has no effect on other nuclear receptor systems tested. Furthermore, the repressor could inhibit the 4-hydroxy-tamoxifen (4OH-T)-induced ER activity. Taken together, our results demonstrate that the inducible repressor we have designed could specifically inhibit ER target gene expression in response to an exogenous synthetic ligand. This repressor will provide a useful tool to study the role of ER target genes in breast cancer progression and it may be potentially useful for gene therapy of breast cancer.
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PMID:Suppression of gene expression by tethering KRAB domain to promoter of ER target genes. 1041 89

Estrogens stimulate the proliferation of many breast tumors and cell lines derived from them. Antiestrogens have therefore become a powerful therapeutic agent to treat breast tumors that express estrogen receptor (ER) alpha. In addition, aromatase inhibitors are now used in postmenopausal women to block the in situ conversion of adrenal androgens to estrogens. This approach can only be successful if ER-alpha in a particular tumor is not directly stimulated by adrenal androgens. We have examined this possibility using several different cell lines as model systems: (a) wild-type MCF7 cells, an ER-alpha-dependent human breast cancer cell line; (b) MCF7SH cells, an estrogen-independent MCF7 variant; (c) Ishikawa cells, an ER-alpha-containing human uterine cell line; (d) ER-negative HeLa cells; and (e) budding yeast. Transactivation assays with transfected ER-alpha reporter genes reveal a direct activation of ER-alpha by dehydroepiandrosterone (DHEA), 5alpha-androstene-3beta,17beta-diol, testosterone, and the two nonaromatizable androgens, dihydrotestosterone and 5alpha-androstane-3beta,17beta-diol. The involvement of other steroid receptors could be ruled out with specific antihormones. Moreover, the same set of ligands stimulates the proliferation of the two breast cancer cell lines. At subsaturating and physiologically relevant concentrations of DHEA, DHEA stimulates the proliferation of MCF7SH cells, which correlates with a substantial, albeit submaximal, transcriptional response. Thus, adrenal androgens must also be considered as risk factors in postmenopausal women.
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PMID:Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of estrogen receptor alpha. 1051 97

Estrogens play a central role in reproductive physiology. The cellular effects of estrogens are mediated by binding to nuclear receptors (ER) which activate transcription of genes involved in cellular growth control. At least two such receptors, designated ERalpha and ERbeta, mediate these effects in conjunction with a number of coactivators. These receptors can directly interact with other members of the steroid receptor superfamily. A complex cross-talk exists between the estrogen-signaling pathways and the downstream signaling events initiated by growth factors, such as epidermal growth factor and insulin-like growth factors. Estrogens are also a causative factor in the pathogenesis of a variety of neoplastic and non-neoplastic diseases, including breast cancer, endometrial cancer, endometriosis, and uterine fibroids, among others. Antiestrogens, such as tamoxifen, are widely used for the treatment of breast cancer. Tamoxifen produces objective tumor shrinkage in advanced breast cancer, reduces the risk of relapse in women treated for invasive breast cancer, and prevents breast cancer in high-risk women. Although, initially developed as an antiestrogen, tamoxifen can also prevent postmenopausal osteoporosis as well as reduce cholesterol, due to its estrogen-agonist effects. Its estrogen-agonist activity, however, can lead to significant side-effects such as endometrial cancer and thromboembolic phenomena. This has led to the concept of "ideal" selective estrogen receptor modulators (SERMs), drugs that would have the desired, tissue selective, estrogen-agonist or -antagonist effects. Raloxifene is a SERM which has the desirable mixed agonist/antagonist effects of tamoxifen but does not cause uterine stimulation. "Pure" antiestrogens may provide very potent estrogen-antagonist drugs, but are likely to be devoid of beneficial effects on bone and lipids. Future drug development efforts should focus on developing superior SERMs that have a greater efficacy against ER-positive tumors and do not cause hot flashes or thromboembolism, and explore combination strategies to simultaneously target hormone-dependent as well as hormone-independent breast cancer.
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PMID:Antiestrogens--tamoxifen, SERMs and beyond. 1066 80

Breast cancer, the most frequent spontaneous malignancy diagnosed in women in the Western world, is a classical model of hormone dependent malignancy. There is substantial evidence that breast cancer risk is associated with prolonged exposure to female hormones, since early onset of menarche, late menopause, hormone replacement therapy and postmenopausal obesity are associated with greater cancer incidence. Among these hormonal influences a leading role is attributed to estrogens, either of ovarian or extra-ovarian origin, as supported by the observations that breast cancer does not develop in the absence of ovaries, ovariectomy causes regression of established malignancies, and in experimental animal models estrogens can induce mammary cancer. Estrogens induce in rodents a low incidence of mammary tumors after a long latency period, and only in the presence of an intact pituitary axis, with induction of pituitary hyperplasia or adenomas and hyperprolactinemia. Chemicals, radiation, viruses and genomic alterations have all been demonstrated to have a greater tumorigenic potential in rodents. Chemical carcinogens are used to generate the most widely studied rat models; in these models hormones act as promoters or inhibitors of the neoplastic process. The incidence and type of tumors elicited, however, are strongly influenced by host factors. The tumorigenic response is maximal when the carcinogen is administered to young and virgin intact animals in which the mammary gland is undifferentiated and highly proliferating. The atrophic mammary gland of hormonally-deprived ovariectomized or hypophysectomized animals does not respond to the carcinogenic stimulus. Administration of carcinogen to pregnant, parous or hormonally treated virgin rats, on the other hand, fails to elicit a tumorigenic response, a phenomenon attributed to the higher degree of differentiation of the mammary gland induced by the hormonal stimulation of pregnancy. In women a majority of breast cancers that are initially hormone dependent are manifested during the postmenopausal period. Estradiol plays a crucial role in their development and evolution. However, it is still unclear whether estrogens are carcinogenic to the human breast. The apparent carcinogenicity of estrogens is attributed to receptor-mediated stimulation of cellular proliferation. Increased proliferation could result in turn in accumulation of genetic damage and stimulation of the synthesis of growth factors that act on the mammary epithelial cells via an autocrine or paracrine loop. Alternatively estrogens may induce cell proliferation through negative feedback by removing the effect of one or several inhibitory factors present in the serum. Multidisciplinary studies are required for the elucidation of the mechanisms responsible for the initiation of breast cancer. Understanding of such mechanisms is indispensable for developing a rational basis for its prevention and control.
J Mammary Gland Biol Neoplasia 1998 Jan
PMID:Role of hormones in mammary cancer initiation and progression. 1081 4

Estrogens and progesterone, acting via their specific nuclear receptors, are essential for normal mammary gland development and differentiated function. The molecular mechanisms through which these effects are mediated are not well defined, although significant recent progress has been made in linking steroid hormone action to cell cycle progression. This review summarizes data identifying c-myc and cyclin D1 as major downstream targets of both estrogen- and progestin-stimulated cell cycle progression in human breast cancer cells. Additionally, estrogen induces the formation of high specific activity forms of the cyclin E-Cdk2 enzyme complex lacking the cyclin-dependent kinase (CDK)3 inhibitor, p21. The delayed growth inhibitory effects of progestins, which are likely to be prerequisites for manifestation of their function in differentiation, also involve decreases in cyclin D1 and E gene expression and recruitment of CDK inhibitors into cyclin D1-Cdk4 and cyclin E-Cdk2 complexes. Thus estrogens and progestins affect CDK function not only by effects on cyclin abundance but also by regulating the recruitment of CDK inhibitors and, as yet undefined, additional components which determine the activity of the CDK complexes. These effects of estrogens and progestins are likely to be major contributors to their regulation of mammary epithelial cell proliferation and differentiation.
J Mammary Gland Biol Neoplasia 1998 Jan
PMID:Estrogen and progestin regulation of cell cycle progression. 1081 5

Estrogens are important for the development of the mammary gland and strongly associated with oncogenesis in this tissue. The biological effects of estrogens are mediated through the estrogen receptor (ER), a member of the nuclear receptor superfamily. The estrogen/ER signaling pathway plays a central role in mammary gland development, regulating the expression and activity of other growth factors and their receptors. The generation of the ER knockout (ERKO) mouse has made it possible to directly understand the contribution of ER in mammary development and has provided an unique opportunity to study estrogen action in carcinogenesis. A mammary oncogene (Wnt-1) was introduced into the ERKO background to determine if the absence of the ER would affect the development of tumors induced by oncogenic stimulation. The development, hyperplasia, and tumorigenesis in mammary glands from the ERKO/Wnt-1 mouse line are described. These studies provide the impetus to evaluate the effect of other oncogenes in mammary tumorigenesis in the absence of estrogen/ER signaling.
J Mammary Gland Biol Neoplasia 1997 Oct
PMID:Mammary gland development and tumorigenesis in estrogen receptor knockout mice. 1093 20


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