2005-11-02
Estrogen Receptor Signaling in the Endometrium: pathway analysis of agonists and antagonists
Publication
Publication
Oestrogeen receptor signaaltransductie in het endometrium : werking van agonisten en antagonisten
Endometrial cancer is the most common gynecological malignancy in Europe and the USA. In the normal endometrium, growth and differentiation is controlled by the ovarian hormones estrogen and progesterone. After menopause, the absence of follicle recruitment in the ovary results in a decline in serum levels of estrogen and progesterone, and consequently results in an atrophic/inactive state of the endometrium. However, in some women increased levels of estrogen (either endogenous or exogenous) are present, which will stimulate the endometrium. This estrogen-induced growth of the endometrium may result in uncontrolled growth, which can eventually develop into cancer. As in the normal endometrium, progesterone inhibits growth of endometrial cancer cells and is therefore used in the clinic as adjuvant therapy. Tamoxifen, a selective estrogen receptor modulator (SERM), is standard adjuvant therapy for patients with estrogen receptor positive (ER+) breast cancer (estrogen-antagonistic effect). In the endometrium, however, tamoxifen displays an estrogen-agonistic effect, and use of tamoxifen is therefore associated with an increased risk for development of endometrial pathologies, including endometrial cancer. For the endometrium, but also for many other organs, growth factors and growth factor receptors play a central role in mediating the effects of steroid hormones. Growth factors like IGF-1 and EGF mediate estrogen receptor signaling and are therefore also involved in the regulation of proliferation of the endometrium and endometrial cancer. The emphasis of this thesis is on the molecular mechanisms of estrogen receptor controlled proliferation of the human endometrium and subsequent induction of endometrial cancer. We postulated and addressed the following questions in this thesis: 1. What are the molecular mechanisms underlying estrogen-induced growth stimulation and progesterone-induced growth inhibition of endometrial cancer cells? 2. Does activation of the ER signaling pathway result in activation of IGF and/or EGF signaling, and vice versa, does activation of the IGF and EGF signaling pathways result in activation of ER signaling? 3. Which genes are regulated by estrogen, tamoxifen, raloxifene and the anti-estrogen ICI182780 in endometrial cancer cells, and do the four ER-ligands regulate similar genes, in the same cellular processes or pathways? 4. Which genes are regulated in endometrial tissues of tamoxifen-users compared to nonusers, and can we, based on the generated gene-expression profiles, elucidate which pathways are activated by tamoxifen during the early changes which may lead to endometrial cancer formation?
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hdl.handle.net/1765/7179 | |
Organisation | Erasmus MC: University Medical Center Rotterdam |
Gielen, S. (2005, November 2). Estrogen Receptor Signaling in the Endometrium: pathway analysis of agonists and antagonists. Retrieved from http://hdl.handle.net/1765/7179 |