Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of tamoxifen, widely used as adjuvant chemotherapy for breast cancer, increases significantly the risk of developing endometrial cancer. The miscoding properties of tamoxifen-derived DNA adducts, alpha-(N2-deoxyguanosinyl)tamoxifens (dG-N2-tamoxifen), have been explored, using an in vitro experimental system to quantify base substitutions and deletions. Site-specifically modified oligodeoxynucleotides containing an epimer of trans- and cis-forms of dG-N2-tamoxifens were prepared postsynthetically and used as templates in primer extension reactions catalyzed by mammalian DNA polymerases alpha, beta, and delta. Pol alpha catalyzed incorporation of dCMP and dAMP opposite all four stereoisomers of dG-N2-tamoxifen, accompanied by lesser amounts of dGMP. In contrast, pol delta catalyzed preferential incorporation of dCMP, a correct base, opposite the lesions; one of the trans-forms of dG-N2-tamoxifens only promoted incorporation of dTMP. Using pol beta, preferential incorporation of dCMP, along with small amounts of incorporation of dAMP and dGMP, was detected. One- and two base deletions were also observed with pol alpha and pol beta. The miscoding specificities and frequencies of dG-N2-tamoxifens varied depending on the DNA polymerase used. In addition, with pol alpha and pol beta, large amounts of 5-base deletions were preferentially formed at the cis-forms of dG-N2-tamoxifen, but not at the trans-forms of dG-N2-tamoxifen. We conclude that dG-N2-tamoxifen adducts have high miscoding potentials.
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PMID:Miscoding potential of tamoxifen-derived DNA adducts: alpha-(N2-deoxyguanosinyl)tamoxifen. 933 62

Forty years ago, Lerner and coworkers (1958) discovered the first nonsteroidal antiestrogen and Jensen (Jensen and Jacobson, 1960) identified a target for drug action, the ER. This knowledge opened the door for the clinical development of tamoxifen which we now know provides a survival advantage in both node-positive and node-negative patients with ER-positive disease (Early Breast Cancer Trialists Collaborative Group, 1992, 1998). The drug has been studied extensively, and the results have provided an invaluable insight into possible ancillary advantages of "antiestrogens", i.e., maintenance of bone density and the prevention of coronary heart disease, and possible disadvantages, i.e., rat liver carcinogenesis and an increased risk of endometrial cancer. Most importantly, the identification of the target site-specific actions of tamoxifen caused a paradigm shift in the prospective uses of antiestrogens from a direct exploitation of the antitumor properties to the broader application as a preventative for osteoporosis, but with the beneficial side effects of preventing breast and endometrial cancer. Raloxifene, a second-generation SERM, has all the properties in the laboratory that would encourage development as a safe preventative for osteoporosis (Jordan et al., 1997). As a result, raloxifene has been evaluated in more than 11,000 postmenopausal women and found to maintain bone density with significant decreases in breast cancer incidence and no increase in endometrial thickness. Raloxifene is now available as a preventative for osteoporosis in postmenopausal women. There is every reason to believe that a multifaceted agent like raloxifene will find widespread use, and there will be continuing interest by the pharmaceutical industry in the development of new agents with even broader applications. The extensive clinical effort is augmented by past molecular innovations in the laboratory and the future promise of new discoveries. The cloning and sequencing of the ER (Green et al., 1986; Greene et al., 1986) has allowed the development of an ER knock-out mouse (Lubahn et al., 1993) that compliments Jensen's pioneering work (Jensen and Jacobson, 1962) and describes the consequences of the loss of ER alpha. However, ER beta (Kuiper et al., 1996), the second ER, has provided an additional dimension to the description of estrogen and antiestrogen action. For the future, the development of ER beta monoclonal antibodies, the classification of target sites for the protein around the body, and the creation of ER beta and ER alpha, beta knock-out mice will identify new therapeutic targets to modulate physiological functions. Clearly, the successful crystallization of ER alpha with raloxifene (Brzozowski et al., 1997) must act as a stimulus for the crystallization of ER beta. The central issue for research on antiestrogen pharmacology is the discovery of the mechanism (or mechanisms) of target site-specificity for the modulation of estrogenic and antiestrogenic response. The description of a stimulatory pathway for antiestrogens through an AP-1 ER beta signal transduction pathway (Paech et al., 1997), although interesting, may not entirely explain the estrogenicity of antiestrogens. The model must encompass the sum of pharmacological consequences of signal transduction through ER alpha and ER beta with the simultaneous competition from endogenous estrogens at both sites. This is complicated because estradiol is an antagonist at ER beta through AP-1 sites (Paech et al., 1997), so this is clearly not the pathway for estrogen-induced bone maintenance in women. Estrogen is stimulatory through ER alpha, but antiestrogens are usually partial agonists and may either block or stimulate genes. However, we suggest that the ER alpha stimulatory pathway could be amplified through selective increases in coactivators. The principle is illustrated with the MDA-MB-231 cells stably transfected with the cDNAs for the wild-type and the amino acid 351 mutan
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PMID:Basic guide to the mechanisms of antiestrogen action. 964 65

Retinoids have recently been proposed to modulate estrogenic actions in various sex steroid-dependent neoplasms, but little has been studied in human endometrial disorders. Therefore, in this study, we first examined the immunolocalization of retinoic acid receptor alpha, beta, and gamma, and retinoid X receptor (RXR) alpha, beta, and gamma in 20 normal cycling human endometria, 34 endometrial hyperplasia, and 46 endometrioid endometrial adenocarcinomas. We then correlated these findings with other clinicopathological parameters, especially in the correlation between retinoid receptor subtypes and the status of steroid hormone receptors, 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) and aromatase. We also then examined the effects of retinoic acid on the expression of 17 beta-HSD type 2 in cell lines derived from endometrial carcinoma using Northern blotting analysis to examine the possible roles of retinoids in in situ endometrial estrogen metabolism. Among these six retinoid receptors examined, RXR gamma immunoreactivity was exclusively detected in the epithelial cells of the secretory phase endometrium but not of the proliferative phase, which was well correlated with 17 beta-HSD type 2 immunolocalization. However, in endometrial hyperplasia, RXR gamma was not correlated with 17 beta-HSD type 2. In endometrioid endometrial adenocarcinoma, there was a statistically significant correlation between 17 beta-HSD type 2 immunoreactivity and RXR gamma labeling index (LI) (P < 0.001) and between RXR gamma LI and progesterone receptor LI (r = 0.501, P = 0.003). A significant inverse correlation was also detected between RXR gamma LI and patient age (r = 0.449, P = 0.015). No statistically significant correlation was obtained between LIs of receptors and other clinicopathological parameters including the status of intratumoral aromatase examined by immunohistochemistry. In the endometrial carcinoma cell line, RL95-2, retinoic acid markedly increased the level of 17 beta-HSD type 2 messenger RNA in a time- and dose-dependent manner. These results all suggest that retinoic acids may be involved in modulation of in situ estrogen metabolism in both normal and neoplastic human endometrium possibly through RXR gamma by stimulating the expression of 17 beta-HSD type 2.
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PMID:Retinoid receptors in the human endometrium and its disorders: a possible modulator of 17 beta-hydroxysteroid dehydrogenase. 1139 77