Dual role of estrogens in endometrial cancer
Abstract
Increased local concentrations of estrogens are a well-known risk factor for endometrial cancer. Estrogens can act as mitogens via the estrogen receptors, and by forming oxidative metabolites they can act as cancer initiators. The role of estrogens differs with the stage of the disease. In pre-cancerous endometrium, estrogens are converted into estrogen quinones, which are potent carcinogens and can act as cancer initiators. Estrogen quinones can react with DNA and cause DNA depurination. They are also involved in the formation of reactive oxygen species, which can additionally damage DNA and other cellular macromolecules. In fully developed cancers, the role of estrogens is mainly to stimulate cell proliferation and to inhibit apoptosis, which also increases the occurrence of random errors in DNA replication. Estrogen actions are regulated at the receptor level as well as at the levels of the estrogen biosynthesizing and metabolizing enzymes. These latter represent potential targets for the development of new therapeutics, while the oxidative metabolites of estrogens can serve as biomarkers for diagnosis and monitoring of endometrial cancer.Downloads
References
Rak v Sloveniji 2009. Ljubljana: Onkološki inštitut Ljubljana, Epidemiologija in register raka, Register raka Republike Slovenije; 2013.
Ferlay J, S.H., Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. 2010 [cited 2013 27/05/2013].
Tsikouras, P., Bouchlariotou, S., Vrachnis, N., Dafopoulos, A., Galazios, G., Csorba, R., et al. Endometrial cancer: molecular and therapeutic aspects. Eur J Obstet Gynecol Reprod Biol 2013.
Liu, F.S. Molecular carcinogenesis of endometrial cancer. Taiwan J Obstet Gynecol 2007; 46 (1): 26-32.
Samarnthai, N., Hall, K., Yeh, I.T. Molecular profiling of endometrial malignancies. Obstet Gynecol Int 2010; 2010: 162363.
Berstein, L.M., Tchernobrovkina, A.E., Gamajunova, V.B., Kovalevskij, A.J., Vasilyev, D.A., Chepik, O.F., et al. Tumor estrogen content and clinico-morphological and endocrine features of endometrial cancer. J Cancer Res Clin Oncol 2003; 129 (4): 245-9.
Dossus, L., Lukanova, A., Rinaldi, S., Allen, N., Cust, A.E., Becker, S., et al. Hormonal, metabolic, and inflammatory profiles and endometrial cancer risk within the EPIC cohort--a factor analysis. Am J Epidemiol 2013; 177 (8): 787-99.
Engelsen, I.B., Akslen, L.A., Salvesen, H.B. Biologic markers in endometrial cancer treatment. APMIS 2009; 117 (10): 693-707.
Amant, F., Moerman, P., Neven, P., Timmerman, D., Van Limbergen, E., Vergote, I. Endometrial cancer. Lancet 2005; 366 (9484): 491-505.
King, A.E., Critchley, H.O. Oestrogen and progesterone regulation of inflammatory processes in the human endometrium. J Steroid Biochem Mol Biol 2010; 120 (2-3): 116-26.
Bolton, J.L., Thatcher, G.R. Potential mechanisms of estrogen quinone carcinogenesis. Chem Res Toxicol 2008; 21 (1): 93-101.
Yager, J.D., Davidson, N.E. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006; 354 (3): 270-82.
Lanišnik Rižner, T. Estrogen biosynthesis, phase I and phase II metabolism, and action in endometrial cancer. Mol Cell Endocrinol 2013; 381 (1-2): 124-39.
Cavalieri, E., Chakravarti, D., Guttenplan, J., Hart, E., Ingle, J., Jankowiak, R., et al. Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta 2006; 1766 (1): 63-78.
Hevir, N., Šinkovec, J., Lanišnik Rižner, T. Disturbed expression of phase I and phase II estrogen-metabolizing enzymes in endometrial cancer: Lower levels of CYP1B1 and increased expression of S-COMT. Mol Cell Endocrinol 2011; 331 (1): 158-67.
Lepine, J., Audet-Walsh, E., Gregoire, J., Tetu, B., Plante, M., Menard, V., et al. Circulating estrogens in endometrial cancer cases and their relationship with tissular expression of key estrogen biosynthesis and metabolic pathways. J Clin Endocrinol Metab 2010; 95 (6): 2689-98.
Bochkareva, N.V., Kolomiets, L.A., Kondakova, I.V., Stukanov, S.L., Starova, A.B., Agarkova, L.A. Enzymes of estrogen metabolism in endometrial cancer. Bull Exp Biol Med 2006; 141 (2): 240-2.
Secky, L., Svoboda, M., Klameth, L., Bajna, E., Hamilton, G., Zeillinger, R., et al. The sulfatase pathway for estrogen formation: targets for the treatment and diagnosis of hormone-associated tumors. J Drug Deliv 2013; 2013.
Coelingh Bennink, H.J. Are all estrogens the same? Maturitas 2004; 47 (4): 269-75.
Lanišnik Rižner, T. Estrogen metabolism and action in endometriosis. Mol Cell Endocrinol 2009; 307 (1-2): 8-18.
Prehn, C., Moller, G., Adamski, J. Recent advances in 17beta-hydroxysteroid dehydrogenases. J Steroid Biochem Mol Biol 2009; 114 (1-2): 72-7.
Raftogianis, R., Creveling, C., Weinshilboum, R., Weisz, J. Chapter 6: Estrogen metabolism by conjugation. in J Natl Cancer Inst Monogr; 2000; 27: 113-24.
Zhu, B.T., Conney, A.H. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998; 19 (1): 1-27.
Audet-Walsh, E., Lepine, J., Gregoire, J., Plante, M., Caron, P., Tetu, B., et al. Profiling of endogenous estrogens, their precursors, and metabolites in endometrial cancer patients: association with risk and relationship to clinical characteristics. J Clin Endocrinol Metab 2011; 96 (2): E330-9.
Lukanova, A., Lundin, E., Micheli, A., Arslan, A., Ferrari, P., Rinaldi, S., et al. Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. Int J Cancer 2004; 108 (3): 425-32.
Hevir, N. Študije metabolizma estrogenov in progesterona pri raku endometrija in ovarijski endometriozi [doktorsko delo]. Ljubljana: Univerza v Ljubljani; 2011.
Šmuc, T., Lanišnik Rižner, T. Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer. Mol Cell Endocrinol 2009; 301 (1-2): 74-82.
Knapp, P., Chabowski, A., Blachnio-Zabielska, A., Walentowicz-Sadlecka, M., Grabiec, M., Knapp, P. Expression of Estrogen Receptors (alpha, beta), Cyclooxygenase-2 and Aromatase in normal endometrium and endometrioid cancer of uterus. Adv Med Sci 2013: 1-8.
Ito, K., Utsunomiya, H., Niikura, H., Yaegashi, N., Sasano, H. Inhibition of estrogen actions in human gynecological malignancies: new aspects of endocrine therapy for endometrial cancer and ovarian cancer. Mol Cell Endocrinol 2011; 340 (2): 161-7.
Fournier, M.A., Poirier, D. Estrogen formation in endometrial and cervix cancer cell lines: involvement of aromatase, steroid sulfatase and 17beta-hydroxysteroid dehydrogenases (types 1, 5, 7 and 12). Mol Cell Endocrinol 2009; 301 (1-2): 142-5.
Cornel, K.M., Kruitwagen, R.F., Delvoux, B., Visconti, L., Van de Vijver, K.K., Day, J.M., et al. Overexpression of 17beta-hydroxysteroid dehydrogenase type 1 increases the exposure of endometrial cancer to 17beta-estradiol. J Clin Endocrinol Metab 2012; 97 (4): E591-601.
Lee, A.J., Cai, M.X., Thomas, P.E., Conney, A.H., Zhu, B.T. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 2003; 144 (8): 3382-98.
Cavalieri, E.L., Rogan, E.G. Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. J Steroid Biochem Mol Biol 2011; 125 (3-5): 169-80.
Al-Gubory, K.H., Fowler, P.A., Garrel, C. The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol 2010; 42 (10): 1634-50.
Lepine, J., Bernard, O., Plante, M., Tetu, B., Pelletier, G., Labrie, F., et al. Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J Clin Endocrinol Metab 2004; 89 (10): 5222-32.
Gaikwad, N.W., Rogan, E.G., Cavalieri, E.L. Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic Biol Med 2007; 43 (9): 1289-98.
Singh, M.N., Stringfellow, H.F., Walsh, M.J., Ashton, K.M., Paraskevaidis, E., Abdo, K.R., et al. Quantifiable mRNA transcripts for tamoxifen-metabolising enzymes in human endometrium. Toxicology 2008; 249 (1): 85-90.
Hevir, N., Ribic-Pucelj, M., Lanisnik Rizner, T. Disturbed balance between phase I and II metabolizing enzymes in ovarian endometriosis: a source of excessive hydroxy-estrogens and ROS? Mol Cell Endocrinol 2013; 367 (1-2): 74-84.
Chan, Q.K., Khoo, U.S., Chan, K.Y., Ngan, H.Y., Li, S.S., Chiu, P.M., et al. Promoter methylation and differential expression of pi-class glutathione S-transferase in endometrial carcinoma. J Mol Diagn 2005; 7 (1): 8-16.
Svoljšak, K. Ugotavljanje prisotnosti encimov za detoksifikacijo estrogenkinonov pri raku endometrija [diplomsko delo]. Ljubljana: Univerza v Ljubljani; 2013.
The Author transfers to the Publisher (Zdravniški vestnik/Slovenian Medical Journal) all economic copyrights following form Article 22 of the Slovene Copyright and Related Rights Act (ZASP), including the right of reproduction, the right of distribution, the rental right, the right of public performance, the right of public transmission, the right of public communication by means of phonograms and videograms, the right of public presentation, the right of broadcasting, the right of rebroadcasting, the right of secondary broadcasting, the right of communication to the public, the right of transformation, the right of audiovisual adaptation and all other rights of the author according to ZASP.
The aforementioned rights are transferred non-exclusively, for an unlimited number of editions, for the term of the statutory
The Author can make use of his work himself or transfer subjective rights to others only after 3 months from date of first publishing in the journal Zdravniški vestnik/Slovenian Medical Journal.
The Publisher (Zdravniški vestnik/Slovenian Medical Journal) has the right to transfer the rights, acquired parties without explicit consent of the Author.
The Author consents that the Article be published under the Creative Commons BY-NC 4.0 (attribution-non-commercial) or comparable licence.
