Projects / Programmes
Molecular basis of endometriosis and endometrial cancer
| Code |
Science |
Field |
Subfield |
| 3.07.00 |
Medical sciences |
Metabolic and hormonal disorders |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
endometriosis, endometrial cancer, estrogens, progestagens, pre receptor regulation
Researchers (12)
Organisations (2)
Abstract
Endometriosis and endometrial cancer are very common estrogen dependent diseases. Endometriosis affects around 15-20% of women in the reproductive age and the incidence increases to 30-50% in patients with infertility. Endometrial cancer is the most common malignancy of the female genital tract, with the majority of cases arising in postmenopausal women. This hormone dependent type of cancer is the fourth most common cancer in women in Western Europe, the USA, as well as in Slovenia. In endometriosis and endometrial cancer are genes, that are involved in estrogen and progesterone metabolism and action, aberrantly expressed, thus affecting estradiol (Eol) and progesterone (P) metabolism and concentrations within the ectopic and the cancerous endometrium. The increased local concentrations of Eol lead to proliferation of endometrium and the decreased P levels can not oppose the estrogen action. With this project we will test the hypothesis concerning the increased levels of Eol and decreased levels of P in the ectopic and the cancerous endometrium in comparison to the normal endometrium. We will examine expression of genes involved in Eol biosynthesis via the aromatase and the sulfatase pathway, genes involved in P metabolism, as well as genes coding for ER/, PRa/b, their coactivators and corepressors in the ectopic and the cancerous endometrium in comparison to the normal endometrium. Expression will be followed at the mRNA and the protein levels. The putative colocalization of the pre-receptor regulatory enzymes and the corresponding receptors will also be examined. The selected enzymes up-regulated in the ectopic or the cancerous endometrium, potential new drug targets, will be prepared in a recombinant form to enable further study of potential inhibitors. Proteome of blood plasma of enometriosis and endometrial cancer patients as well as of healthy individuals will also be studied to identify specific proteins that may serve as new molecular markers and may be beneficial for non-invasive diagnostics.
Significance for science
We tested the hypothesis of increased local concentrations of estrogens and decreased concentrations of progesterone (P) in endometriosis tissue and cancerous endometrium. We successfully identified differentially expressed genes of estradiol (E2) biosynthesis and P metabolism at the mRNA and the protein levels in samples of ectopic and cancerous endometrium. As enzymes of E2 biosynthesis and P metabolism regulate estrogen and P action at the pre-receptor level, we also examined the expression of estrogen and progesterone receptors (ERalfa/ERbeta and PRA/PRB). We also studied local biosynthesis of E2 from androstenedione and estrone and determined local concentrations of androstenedione and E2 in cancerous and adjacent control endometrium. Expression analysis at the mRNA and protein levels revealed that in endometrial cancer E2 can be formed only via the sulfatase pathway, while in endometriosis pathways, the aromatase and the sulfatase have impotant role in local E2 formation. Our results also showed disturbed P metabolism in endometriosis and endometrial cancer and thus decreased protective effects. The expression of genes identified as up-regulated correlated with the expression and localization of ERalfa/ERbeta and PRA/B, suggesting that the pre-receptor regulation is affected in diseased tissue. The differentially expressed genes thus represent potential novel drug targets for treatment of endometriosis and endometrial cancer. The identified enzymes coded by differentially expressed genes were prepared in the recombinant forms which enabled further inhibition studies. In collaboration with Faculty of Pharmacy (Prof. S. Gobec) we examined a series of structurally diverse compounds as inhibitors of these enzymes and found inhibitors with microM and nM Ki values that could serve as lead compounds for further optimizations. Differential expression of receptors ERalfa/ERbeta and PRA/PRB in endometriosis and endometrial cancer further indicate that regulation of estrogen and P action at the receptor level is affected as well, and thus, also agonists or antagonists of ER and PR represent possible new drug targets. We thus clarified the role of enzymes of the aromatase and the sulfatase pathway, enzymes of P metabolism, receptors ERalfa/ERbeta, and PRa/PRb in pathogenesis of endometriosis and endometrial cancer. Our studies also contributed to a better understanding of the molecular basis of endometriosis and endometrial cancer and showed that in endometriosis and endometrial cancer both pre-receptor and receptor regulation of estrogen and P action are affected.
Significance for the country
We identified novel potential targets for design of drugs for treatment of endometriosis and endometrial cancer. The cell specific expression of estrogen and progesterone (P) metabolizing enzymes enables development of selective intracrine modulators (SIM), inhibitors that prevent biosynthesis and steroid hormone action at the pre-receptor level. Better understanding of ERalfa/ERbeta and PRA/PRB expression in endometriosis and endometrial cancer also contributes to development of selective modulators of ER and PR (SERM, SPRM). The incidence of endometriosis and endometrial cancer in Slovenia is very high, showing high significance of these studies. In Slovenia endometriosis is diagnosed in 40% of infertile patients and the incidence of endometrial cancer (31 /100 000 predicted for year 2009) in Slovenia surmounts the one reported for USA and Western Europe (22.9 in 22.5 / 100 000). Moreover, Slovenia has one of the lowest birth rates in Europe, thus further emphasizing immense importance of these studies for our country. All in all the project will contribute to a better understanding, diagnostics and treatment of these two estrogen dependent diseases. On the other hand, the identification of novel drug targets may be of interest also for Slovenian pharmaceutical industry.
In the framework of J3 9448 project several undergraduate students and Ph.D. students were trained. Eight undergraduate and five Ph.D. students were directly involved in studies of molecular basis of endometriosis and endometrial cancer and several of these students already transferred their knowledge and experience to Slovenian industry. High quality of research of these students was recognized by several awards: two Prešeren awards, two Krka awards and two awards UNESCO and L’Oreal for women in science.
Most important scientific results
Annual report
2008,
2009,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2008,
2009,
final report,
complete report on dLib.si
