PATHOGENETIC MECHANISMS OF BENIGN BREAST DISEASE DEVELOPMENT IN WOMEN OF FERTILE AGE WITH ENDOMETRIAL HYPERPLASIA

Author(s):  
I.M. Ordiyants ◽  
D.G. Aryutin ◽  
A.A. Persidskaya ◽  
R.G. Guseynova ◽  
D.S. Novginov

Proliferative changes in the mammary glands very often associate with gynecological diseases. It is the state of receptors for sex steroids in the tissue but not the absolute concentration of hormones in the blood that influences the development of breast and endometrial diseases. It is still unclear how the structure and properties of estrogen (ER) and progesterone (PR) receptors, associated with ESR1 and PRG gene polymorphisms, change. Thus, a new line of scientific research was the examination of microRNA role in the pathogenesis of benign breast diseases in women of fertile age with endometrial hyperplasia. It is known, that microRNAs are involved in many cellular processes, as they influence target genes. The aim of the study was to determine the prognostic significance of epigenetic markers in benign mammary dysplasia pathogenesis in women of fertile age with endometrial hyperplasia. Materials and Methods. The authors examined 69 women aged 18–49, 27 women with endometrial hyperplasia (EН) without atypia and 42 women with benign mammary dysplasia (BMD) with endometrial hyperplasia without atypia. We studied the expression levels of estrogen and progesterone receptors, and their isoform ratio in the blood serum. We also isolated miR-125b, miR-155, miR-222, and miR-429 by real-time PCR. Results. The prevalence of CC allele of the PvuII C/T polymorphism and GG allele of the Xbal A/G polymorphism in ESR1 gene estrogen receptor causes the BMD in women of fertile age with EH, leading to a decrease in ER sensitivity. Epigenetic changes at the microRNA level indicate a decrease in cell adaptiveness, an increase in their proliferative activity, and an induction of angiogenesis. High expression of miR-155, miR-222, and miR-429 indicates poor prognosis for breast cancer patients. The study of correlation of miR-155, miR-222, and miR-429 with the ESR1 estrogen receptor gene polymorphism showed, that the highest Pvull C/T (TT, TC, and CC) and Xbal A/G (AA, AG, and GG) scores were found in women of fertile age with BMD associated with EH. Conclusion. The results of the molecular genetic studies demonstrate the possibility to predict the occurrence and development of breast proliferative diseases in women of fertile age with endometrial hyperplasia. Key words: benign mammary dysplasia, endometrial hyperplasia, estrogen receptors, progesterone receptors, microRNA. Пролиферативные изменения в молочных железах очень часто возникают на фоне гинекологических заболеваний. Решающее значение в возникновении заболеваний молочных желез и эндометрия имеет не абсолютная концентрация гормонов в крови, а состояние рецепторов к половым стероидам в ткани. Остается открытым вопрос об изменении структуры и свойств эстрогеновых (ER) и прогестероновых (PR) рецепторов, связанных с наличием полиморфизмов кодирующих их генов (ESR1 и PRG). Новым направлением научного поиска стало изучение роли микроРНК в патогенезе доброкачественных заболеваний молочных желез при гиперплазии эндометрия в репродуктивном возрасте. Известно, что микроРНК участвуют во многих клеточных процессах, действуя на специфические гены-мишени. Цель исследования. Определить прогностическую значимость эпигенетических маркеров в патогенезе доброкачественной дисплазии молочных желез при гиперплазии эндометрия в репродуктивном возрасте. Материалы и методы. Было обследовано 69 женщин в возрасте 18–49 лет, из них 27 – с гиперплазией эндометрия (ГЭ) без атипии и 42 – с доброкачественной дисплазией молочных желез (ДДМЖ) при гиперплазии эндометрия без атипии. Исследовали уровни экспрессии эстрогеновых и прогестероновых рецепторов, соотношение их изоформ в сыворотке крови. Произвели выделение miR-125b, -155, - 222, -429 методом ПЦР в режиме real time. Результаты. В основе патогенеза развития ДДМЖ при ГЭ в репродуктивном возрасте лежит преобладание аллеля CC полиморфизма PvuII C/T и аллеля GG полиморфизма Xbal A/G гена ESR1 эстрогенового рецептора, что приводит к снижению чувствительности ER. Эпигенетические изменения на уровне микроРНК свидетельствуют о снижении адаптивных свойств клеток, увеличении их пролиферативной активности, индукции ангиогенеза. Высокая экспрессия miR-155, miR-222 и miR-429 является фактором плохого прогноза для больных раком молочной железы. При изучении взаимосвязи miR-155, -222 и -429 с полиморфизмом гена ESR1 эстрогенового рецептора, самые высокие показатели Pvull C/T (ТТ, ТС и СС) и Xbal A/G (АА, АG и GG) выявлены у женщин с ДДМЖ при ГЭ в репродуктивном возрасте. Выводы. На основании полученных результатов молекулярно-генетических исследований дано научное обоснование возможности прогнозирования возникновения и развития пролиферативных заболеваний молочных желез при гиперплазии эндометрия в репродуктивном возрасте. Ключевые слова: доброкачественная дисплазия молочных желез, гиперплазия эндометрия, эстрогеновые рецепторы, прогестероновые рецепторы, микроРНК.

2018 ◽  
pp. 84-86
Author(s):  
L.V. Pakharenko ◽  

To identify risks of development of any disease is a priority of modern medicine. The article deals with ESR1 gene polymorphisms and its role in the development of premenstrual. The objective: of this study was to investigate the frequency of polymorphic variants of A-351G gene estrogen receptor ESR1 in patients with various forms of premenstrual syndrome. Materials and methods. Molecular genetic analysis of ESR1 gene polymorphism was determines in 50 women with premenstrual syndrome (25 women of them had edematous form of disease, 25 – neuropsychical one; 25 suffered from mild form, 25 – severe one). 25 women without diagnosis of premenstrual syndrome were examined as controls. Results. The study of A-351G polymorphism estrogen gene ESR1 demonstrated no statistically significant differences in the frequency of distribution of genotypes and alleles between women with premenstrual syndrome and without this pathology. However, the frequency of GG genotype in women with severe PMS was significantly higher in 8.0 times compared with healthy women (χ2=4.87; p=0.03) and in women with edematous form of PMS – in 7.0 times (χ2=3.72; p=0.05). Conclusion. Thus, a polymorphic variant of A-351G estrogen receptor gene ESR1 can be regarded as a marker for the development of premenstrual syndrome. Pathological variant GG genotype is significantly associated with the presence of edematous and severe forms of the disease. Key words: premenstrual syndrome, genetic factors, development.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 643-643
Author(s):  
K. Neuss ◽  
D. Elling ◽  
I. Cascorbi ◽  
D. Lueftner

643 Background: The estrogen receptor (ER) is well acknowledged as a prognostic factor in breast cancer, and it is a prerequisite to use the predictive information for hormonal therapy. We investigated whether that the different polymorphisms of the estrogen receptor could influence its expression or functionality. Methods: DNA was extracted from white blood cells of 236 breast cancer patients and 236 healthy, matched controls. The ER genotypes were determined by polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion of the PCR product. Results were shown by electrophoreses. Clinical data such as histologic types, pTNM stage and patients age were available for statistical analyses. Results: We found a statistically significant correlation between the estrogen receptor polymorphism pattern and breast cancer. The receptor type PP was detected statistically significantly more often in postmenopausal breast cancer patients (PP vs pp+Pp, p =0.03). However, there was no correlation to the histobiochemical receptor status or UICC-Stadium. Conclusions: These results show an association between the estrogen receptor polymorphism and breast cancer. It seems to be that a complete lack of the p-allel is a risk factor to develop breast cancer at postmenopausal age. There was no influence on estrogen receptor expression or clinical tumor stage. Thus, we propose that there is no clinical use for estrogen receptor polymorphism analyses at this stage. No significant financial relationships to disclose.


2004 ◽  
Vol 181 (1) ◽  
pp. 77-83 ◽  
Author(s):  
N Fujimoto ◽  
N Jinno ◽  
S Kitamura

Interrelationships between thyroid hormone and estrogen actions have been documented with regard to a variety of physiological functions. Both hormones stimulate transcription of target genes by binding to their nuclear receptors that interact with specific responsive elements (estrogen and thyroid hormone response elements, i.e ERE and TRE, respectively) in the regulatory regions of the gene. In vitro studies have suggested that interplay between the two hormones might be due to cross-talk at hormone responsive elements, with the respective hormone receptors and ligands able to interact, although physiological relevance has yet to be proved. We have proposed a simpler mechanism for thyroid hormone effects on estrogen responses via increase in estrogen receptor alpha (ERalpha) with resultant increase in progesterone receptors, prolactin production and tumor growth. A pituitary cell line, GH3, has been widely used to investigate the function of mammo-somatotropic cells, especially regarding regulation of GH and prolactin production. In the present study, an ERE-luc reporter was transfected into GH3 cells and the responses to endogenous ERalpha were examined. We demonstrated that: (1)l -3,5,3'-triiodothyronine (T3) induces mRNA expression of ERalpha; (2) T3 alone is able to induce ERE-luc activity and this is inhibited by OH-tamoxifen; (3) T3 synergistically acts on estradiol (E2)-induced ERE responses; and (4) ERE-luc activity is enchanted by co-transfection of an ERalpha expression vector. These results support the hypothesis that estrogen responses are potentiated by T3 through up-regulation of ERalpha levels.


1984 ◽  
Vol 70 (2) ◽  
pp. 159-164 ◽  
Author(s):  
Giovanni Di Fronzo ◽  
Vera Cappelletti ◽  
Danila Coradini ◽  
Enrico Ronchi ◽  
Gianfranco Scavone

Estrogen (ER) and progesterone (PgR) receptors were measured simultaneously in 1144 consecutive breast cancer patients to determine the distribution of patients according to receptor and menopausal status when receptor occurrence rates were considered. The prognostic signicance of PgR, either alone or in association with ER, was studied on 187 consecutive breast cancer patients treated only by radical mastectomy. All the cases, as regards axillary node status, were pathologically assessed as node negative. These patients did not receive any adjuvant treatment after mastectomy. At 36 months after mastectomy, the follow-up indicated that PgR- patients have a worse prognosis than PgR+ ones. This is evident when PgR alone is considered as a prognostic factor as well as when it is used to identify, within ER+ cases, those with a higher probability of relapse. In conclusion, it can be stated that although PgR status is an independent prognostic factor, it is useful to evaluate ER and PgR simultaneously for better patient management.


Sign in / Sign up

Export Citation Format

Share Document