Projects / Programmes
The importance of intracrine estrogen action in hormone dependent diseases – impact on therapy
| Code |
Science |
Field |
Subfield |
| 3.07.00 |
Medical sciences |
Metabolic and hormonal disorders |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
hormone dependent diseases, estrogens, menopause, hormone replacement therapy
Researchers (18)
Organisations (2)
Abstract
Hormone dependent cancers as breast cancer (BC), endometrial cancer (EC) and ovarian cancer (OC) represent 35% of all cancers in women. Worldwide, these cancers occur in more than 2.2 million of women/year and comprise 21% of cancer-related deaths/year. Hormone-dependent cancers develop mainly in the postmenopausal women and thus rely on the local formation of active steroid hormones. However, the altered mechanisms of steroid hormone actions in these diseases are still not completely understood. In target organs, active estrogens can be formed from precursor steroid hormones, mainly dehydroepiandrosterone-sulfate (DHEA-S), and estrone-sulfate (E1-S) after their uptake into cells through the transporter proteins of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families and further activation to the most potent estrogen, estradiol by a series of enzymes. On the other hand, the ATP Binding Cassette (ABC) transporters are responsible for active transport of E1-S and DHEA-S from the cells. The combination of altered uptake of steroid precursors, changed intracrine action, in concert with changes in the metabolism and excretion may have major roles in the development of hormone-dependent cancers. Although the importance of estrogens in development of BC have been investigated and partially explained, much less is known about the mechanisms of estrogen action in EC and OC. In particular, the uptake and excretion of precursor steroids and estrogen metabolites via the transporter proteins of the OATP, OAT and ABC families have so far deserved no attention in these two diseases.
Menopause is associated with increased incidence of hormone-dependent cancers, but also with increased risk for osteoporosis, cardiovascular diseases and with characteristic vasomotor symptoms. A large number of women use different phytochemicals as “natural” hormone replacement therapy (HRT) to treat the symptoms and conditions associated with menopause. However, these phytochemicals may interfere with their hormone system, and may thus also affect the risks of EC and OC. Although “natural” HRT including red clover and soy extracts have been widely studied, less is known about black cohosh extracts, especially about their interplay with the uptake of steroid precursors, estrogen biosynthesis and action. The objectives of the proposed project are 1) to examine the uptake of steroid precursors, biosynthesis, metabolism and action of estrogens in model endometrial and ovarian cell lines and corresponding tissues; 2) to explore the effects of “natural” HRT on the uptake of steroid precursors and the intracrine estrogen action in ovarian and endometrial cell lines and 3) to evaluate the systemic effects of “natural” HRT by measuring concentrations of estrogens and estrogen metabolites in blood from postmenopausal women before and after use of “natural” HRT. The aims of this project will be achieved by targeted transcriptomics, proteomics and metabolomics approaches and further modeling studies. The unique aspects of the proposal are 1) use of LC-HMRS which allows simultaneous quantification of steroid precursors, active estrogens and their conjugates; 2) availability of unique OC cell lines as models of sensitive/resistant tumors, and 3) assessment of local and systemic effects of phytochemicals followed by mathematical modelling. The project aims to advance 1) understanding of intracrine estrogen action in development of EC and OC; 2) identification of novel targets for treatment of these diseases and 3) recognition of molecular effects of »natural« HRT. The proposed project will be performed jointly by Faculty of Medicine, University of Ljubljana, University Medical Centre Ljubljana and Faculty of Natural Sciences, University of Vienna and will combine expertise on steroid hormones (Ljubljana), transporter proteins (Vienna) and hormone dependent diseases (Ljubljana).
Significance for science
The role of estrogens in carcinogenesis of breast cancer has been widely studied, but intracrine actions of estrogens in development of endometrial cancer (EC) and especially ovarian cancer (OC) have not been explained yet. These cancers develop mainly in postmenopausal women and thus rely on the local formation of active estrogens from precursor steroid hormones mainly DHEA-S and E1-S after their uptake into cells through the OATP and OAT transporter proteins, while the ATP Binding Cassette (ABC) transporters oppose their action by transport of E1-S and DHEA-S from the cells. So far the roles of DHEA-S and E1-S transporters deserved no attention in these hormone dependent cancers. The project will thus focus on the roles of intracrine estrogen action in development of OC and EC with the special emphasis on the importance of the transporter proteins. The project will include well characterized clinical samples and a unique set of OC cell lines, which represent models of the most frequent high grade serous OC. Also the effects of »natural« HRT on local estrogen formation and action have been rarely studied at the molecular level. We will investigate the effects of the commonly used »natural HRT« - black cohosh extract by targeted transcriptomics, proteomics and metabolomics approaches in endometrial and ovarian model cell lines. The aims of the project will be reached by using a novel approach, the highly sensitive liquid chromatography high-resolution mass spectrometry, which allows for the first time the simultaneous quantification of the parent compounds (DHEA-S and E1-S), active estrogens and their hydrophilic conjugates (glucuronides and sulfates). Additional originality of the proposal is the evaluation of the local and systemic effects of phytochemicals, and especially study of transporters, all combined with further mathematical modelling. The project aims to contribute to 1) a better understanding of intracrine estrogen action in development of hormone dependent cancers; 2) identification of individual transporters or enzymes involved in these processes as novel targets for treatment, and 3) recognition of individual molecules or metabolic steps affected by »natural« HRT, thus providing a blue print for mechanisms of actions of these phytochemicals on estrogen sensitive tissues and a final explanation of their beneficial or harmful effects. By investigating the uptake and excretion of steroid precursors in EC and OC and the effects of phytochemicals on these processes the project will open new avenues in research of these hormone-dependent diseases, which may lead to identification of new strategies for treatment. The importance of the proposed research is showcased also by a Special Issue of the journal Frontiers in Pharmacology (I.F. = 4.8) entitled “Relevance of steroid biosynthesis, metabolism and transport in pathophysiology and drug discovery« which was proposed and is edited by the Slovenian and Austrian P.I. of this project.
Significance for the country
Worldwide, hormone dependent cancers occur in more than 2.2 million of women/year and lead to 750 000 deaths/year (Ferlay, 2013). Endometrial cancer (EC) is the most common gynecological cancer in the developed World with 319 00 cases/year. The most deadly of hormone-dependent cancers is ovarian cancer (OC) with 151 900 deaths/year. Currently only 46% of OC patients survive five years, mainly due to development of resistance to the chemotherapeutic treatments (Bast, 2011). The current treatments of EC and especially OC are thus not optimal and this project may identify novel drug targets among transporters of steroid precursors and estrogen biosynthetic enzymes and may thus pave the way for novel treatment strategies. The findings of this project may also lead to further rational design and synthesis of molecules that would interact with transporters or enzymes and would block proliferation or invasion of cancer cells. Hormone-dependent cancers develop mainly in postmenopausal women. The postmenopausal years constitute one-third of women's lives where population of postmenopausal women ()51 years) will exceed one billion in 2030 (Abdi, 2016). Menopause is associated with increased risk for osteoporosis, cardiovascular diseases and also with vasomotor symptoms. These symptoms occur in as many as 80% of women and may last more than 7 years, thus leading to significantly reduced quality of life and increased healthcare encounters. The menopause associated health problems are prevented or treated by hormone replacement therapy (HRT) (Goldstein, 2016). Since Women Health Initiative and Million Women Study found increased risk for breast cancer among women taking HRT, the use of »natural« alternatives has increased. Also some of the 1.6 million breast cancer patients identified yearly may be using »natural« HRT as tamoxifen treatment exacerbates their menopausal symptoms. A large number of peri/ postmenopausal women with already increased risk for EC and OC are thus exposed to different phytochemicals with unknown effects on intracrine action of estrogens in endometrium and ovaries. Also black cohosh extracts are often used as »natural« HRT. In UK alone 9 million days of treatment with black cohosh extracts is purchased every year. In Slovenia the use of these extracts is even more common with 994 020 days of treatment purchased in 2015, which 3-fold exceeds the use in UK when considering different size of these populations. However, the mechanism of action of these extracts is not fully understood and also the effects on endometrium and ovaries have not been studied at the molecular levels (Merchant, 2015). The proposed project aims to clarify potential beneficial or harmful effects of »natural« HRT on estrogen sensitive tissues, as well as systemic effects, and thus its possible association with EC and OC. In this way our project results may help the clinicians to provide evidence based guidance to menopausal women when considering “natural” HRT.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
