Biomedical subjects

E V Tsyrlina

Publications and source records attributed to E V Tsyrlina.

At least 19 recordsLinked to original sources

PubMed2006

Genotoxic factors associated with the development of receptor-negative breast cancer: potential role of the phenomenon of switching of estrogen effects.

AIM: About 30-40% of breast cancers lack steroid receptors (ER and/or PR) at diagnosis that worsen prognosis and limit the usage of hormone therapy. The aim of this paper has been to study the role of DNA-damaging factors as the potential modifiers of the receptor-negative tumors incidence. MATERIALS AND METHODS: The investigation consisted of two principal parts. In one of them ER and PR content was measured in breast cancer samples from 2284 primary patients (350 of them - current or previous smokers). In separately studied subgroup of 1010 patients 95 suffered with diabetes mellitus type II. RESULTS: As it was shown, smokers and diabetics carry more frequently (p = or < 0.05) tumors with phenotypes ER+PR- and PR- only in the group of women with conserved menstrual cycle that is in case of relatively higher estrogenic stimulation. In another part of the investigation immunohistochemical study of DNA damage marker - 8-hydroxy-2-deoxyguanosine (8-OH-dG) in 16 R(-) and 18 R(+) breast cancer specimens demonstrated more frequent positive staining in the former group of samples (p = 0.05). Besides, as it was revealed in breast cancer cell line MCF-7 the combination of estradiol with aryl hydrocarbonic receptors agonist beta-naphtoflavone induced pronounced genotoxic damage (by 8-OH-dG content) in association with the loss of ER. CONCLUSION: Thus, pro-genotoxic status (smoking, diabetes) and direct signs of genotoxic injury, in accordance with regularities of the phenomenon of switching of estrogen effects can be reckoned among the factors promoting the development of receptor-negative breast cancer.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

[Hormonal and progenotoxic properties of mammary fat in pre- and postmenopausal cancer patients].

Since breast cancer may emerge both before and after menopause onset, relevant forms of the disease show marked biological and clinical differences. Intrinsic properties of mammary fat located in the vicinity of tumor, which play a definitive role in stromal-epithelial interactions, are an important factor of development of such differences. The DNA damage promoting hormonal (leptin and adiponectin production, aromatase activity) and progenotoxic. The properties of mammary fat such as formation of tumor necrosis factor, interleukin-6, nitric oxide, malonic aldehyde, macrophage/histiocyte infiltration and estrogen 4-hydroxylase expression, were studied in mammary fat tissue of 95 patients with receptor-positive or receptor-negative breast tumors (reproductive--25, menopausal--70). It was found that progenotoxic properties might somewhat predominate, as far as differences in parameters and pathways are concerned, both in menopausal and still cycling patients. Hence, progenotoxic damage which represents mammary fat tissue status is perhaps modified by a number of genetic and mitochondrial factors. It may exert unfavorable effect on the course of the disease within a fairly wide period.

Adiponectin↗

PubMed2006

[Correlation of hormone-metabolic status in breast cancer and effectiveness of adjuvant hormone therapy].

Hormono-metabolic status was assayed before and after month 6, 12, 24, 36, 48, 54 and 60 of therapy in 72 patients with receptor-positive tumors of the breast who completed 5 years of adjuvant tamoxifen (20 mg/24 hrs) or letrozole (2.5 mg/24 hrs). Eleven patients were not followed up, 11 relapsed and had metastases while 50 completed therapy. Significant fall in body mass (Ketle's index), in C-peptide concentration after an insignificant rise and C-peptide/insulin ratio 129 min after glucose loading, low basal blood level of estradiol as well as stable estradiolemia throughout treatment were characteristic of cases of pre-treatment recurrence and metastastic spread. Insulin resistance status, basal serum-estradiol level and fasting its course of development during hormonotherapy should be the subject of further research in criteria for adjuvant hormonotherapy efficacy.

Aged↗

PubMed2005

Content of 8-hydroxy-2-deoxyguanosine in steroid receptor-positive and receptor-negative breast cancer cells.

The content of DNA damage marker 8-hydroxy-2-deoxyguanosine in 16 receptor-negative and 18 receptor-positive human breast neoplasms was measured by immunohistochemical methods. Positive staining was revealed in 81.3 and 50.0% samples of groups 1 and 2, respectively. The effect of arylhydrocarbon receptor agonist beta-naphthoflavone on the content of 8-hydroxy-2-deoxyguanosine and number of estrogen and progesterone receptors was evaluated in MCF-7 breast cancer cells. The degree of genotoxic damage significantly increased 1 h after combined treatment with estradiol and beta-naphthoflavone (in contrast to individual treatment) and remained practically unchanged in the follow-up period. According to the estrogen effect-switching phenomenon, genotoxic damage can contribute to the development of R(-)-breast cancer.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2005

[Comparison of letrozole and exemestane used in non-adjuvant therapy of endometrial carcinoma].

The clinical and endocrine-related effects of 2-week preoperative treatment of endometrial carcinoma patients with a non-steroid inhibitor of letrozole aromatase (femara 2.5 mg/day, n=10) and a steroid inactivator of the enzyme (exemestane 25 mg/day, n=13) were compared. In the first group, pain relief in the lower part of the belly and/or decreased uterine discharge were reported in two cases, as well as a 31% drop in the mean endometrial M-echo (ultrasound) signal. In the exemestane group, two patients revealed moderate uterine discharge decrease matched by a 15.6% decrease in M-signal intensity; no tumor was detected in another patient on completion of the course. Letrozole effect was relatively greater when such parameters as tumor-tissue aromatase level, estrogen concentration in vaginal smear and blood-cholesterol, FSH and LH levels were taken into consideration. However, exemestane therapy involved a relatively sharper drop in the levels of tumor receptors of progesterone and a significantly higher estrogen/progesterone receptor ratio. Hence, no matter how short treatment duration was, both steroid and non-steroid aromatase inhibitors induced effects predominantly associated with lowering estrogen production in endometrial carcinoma patients. This makes a case for further clinical trials of these drugs to deal with the pathology.

Androstadienes↗

PubMed2005

[Breast cancer receptor status in smoking and diabetic patients].

Estrogen (ER) and progesterone (PR) receptor levels were assayed in 2,284 primary breast cancer patients who either smoked (350) or suffered diabetes mellitus type 2 (1997-2003). In a group of 1010, 95 patients had diabetes mellitus type 2 whereas 393--such signs of cardiovascular pathology as atherosclerosis, arterial hypertension and ischemic heart disease (2000-2003). Among the premenopausal smokers, the ER+PR-phenotype predominated (t = 2.18, p < 0.05) as well as among the diabetics (t = 2.01, p < 0.05). In reproductive diabetics, the share of PR- tumors was significantly higher than in diabetes-free patients (t = 2.17, p < 0.05). There was no correlation between diabetes and the tumor receptor phenotype in the menopausal group, while ER + tumors--occurred more frequently in smokers (t = 2.33, p = 0.02). There was no link between cardiovascular pathology and receptor status in either of the age groups. Hence, the increasing proportion of ER + PR--tumors in smokers and diabetes mellitus patients occurs in a random manner in menstruating women, which is associated with elevated estrogenemia. This indicates the phenomenon of switching of estrogen effects involving disturbed transduction of estrogen signals.

Adult↗

PubMed2004

Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer.

OBJECTIVES: To study the frequency of insulin resistance (IR) in endometrial cancer patients, its relation to the clinical course of the disease and DNA damage, and to evaluate possible approaches to the pharmacological correction of IR in the patients studied. METHODS: The signs of insulin resistance syndrome and its association with the clinical and pathological features of the disease and DNA damage in somatic cells (micronucleus frequency in peripheral blood lymphocytes) and endometrial normal and tumor tissue (alkaline unwinding) were determined in 99 endometrial cancer patients. RESULTS: The frequency of insulin resistance syndrome counted on the basis of fasting plasma glucose and insulin concentrations according to Duncan et al. is equal to 0.35 (95% CI 0.24-0.46), or 35%, in endometrial cancer patients who do not have a history of diabetes mellitus. Patients with well- or moderately differentiated endometrial adenocarcinomas (mostly type I) had statistically significantly higher basal and stimulated plasma insulin and C-peptide concentrations than patients with poorly differentiated endometrial adenocarcinomas or rarely encountered tumors of the endometrium (primarily type II). Interestingly, the level of fasting insulinemia positively correlates with disease stage and with local and regional tumor dissemination only in the group of patients with well- or moderately differentiated endometrial adenocarcinomas. On the other hand, hyperinsulinemia and other hormonal-metabolic disturbances typical of insulin resistance syndrome do not increase the probability of DNA damage of somatic cells (according to the data of micronucleus test). In addition, no association between hormonal-metabolic disturbances and the degree of DNA unwinding in tumor and visually unchanged endometrium was found. CONCLUSION: Thus, insulin resistance/hyperinsulinemia is associated with a more aggressive course of the disease in certain groups of the patients but--in contrast to excessive estrogenic stimulation--does not result in increased genotoxic damage in tumor and normal tissues. The data obtained once more confirm the need for treatment and prevention measures aimed at correcting hormonal-metabolic disturbances in endometrial cancer patients and groups at risk of this disease. Such an approach might include use of antidiabetic biguanides, thiazolidinediones (glitazones), and statins.

Adenocarcinoma↗

PubMed2004

Expression of estrogen receptors-alpha and -beta in primary breast neoplasms and tumors exposed to neoadjuvant hormonal therapy.

We studied the content and expression of mRNA for estrogen receptors-alpha and -beta in breast tumors before and after 3-month neoadjuvant hormone therapy with antiestrogen tamoxifen and/or aromatase inhibitors. Expression of estrogen receptors-alpha and -beta was most often detected in ER+PR+ tumors and most significantly decreased in these neoplasms after exemestane therapy. Immunocytochemical and radioligand assays showed that tamoxifen and anastrozole have little effect on the number of estrogen receptors-alpha. The number of progesterone receptors in tumors decreased by the end of anastrozole therapy. Estrogen receptors-beta were immunocytochemically revealed in 50% primary breast tumors. Anastrozole slightly decreased, while tamoxifen increased the incidence of these receptors. Interruption of signaling through estrogen receptors and suppression of estrogen biosynthesis had different effects on the receptor status of neoplasms and distribution of estrogen receptors-alpha and -beta.

Anastrozole↗

PubMed2004

[Genetic polymorphism of steroidogenic enzymes and steroid receptor level in tumors of the reproductive system].

The strategy of therapy and prognosis of reproductive system neoplasia generally depend on the steroid receptor status of tumor. The causes of formation of steroid receptor-free tumors are to be investigated. The genetic polymorphism of CYP19 (aromatase), CYP17 (17-hydroxylase; 17,20-lyase), CYP1B1 (4-estrogen hydroxylase) and COMT (catechol-O-methyl transferase) was studied in a total of 254 patients with breast and endometrial cancer, with particular reference to the association of certain polymorphisms and receptor status of tumor. It was found that the lack of estrogen receptor (ER) in breast tumor was due to a deficit in the A3A6 allele (p(0.01), while the absence of progesterone receptors was associated with a lower incidence of the A1A1 and A1A2 variants (p = 0.022) of tetranucleotide repeats in the CYP19 gene. In the same patients, receptor-negative tumors occurred more often (p = 0.032) than in combinations of higher level of 4-hydroxylase estradiol of S-allele in position 48 (Gly/Arg) of the CYP1B1 gene. Moreover, endometrial carcinoma patients tended to reveal (p = 0.058) an increased ratio of A6A7-CYP19 to allele A1-containing variant. No other distinctions between R(+) and R(-) tumors were identified. It is suggested that peculiar polymorphisms of steroidogenic enzymes may moderately influence the genesis of R(-) neoplasms which may be associated with either the rate of estrogen biosynthesis or, as in the case of CYP1B1, with formation of genotoxic derivatives of estrogens. The latter point is to be investigated further.

Adult↗

PubMed2004

[Gail's coefficient in breast cancer patients with respect to menstrual status, body mass and estrogen receptor pattern of tumor].

Groups at high risk for breast cancer are generally identified using Gail's coefficient (GC) which is calculated on the basis of up-to-date age, recorded menarche, at primapara age, having kinswomen with breast cancer, number of biopsy examinations and morphological evidence of atypical hyperplasia of the breast in case history. We established GC versus estrogen receptor pattern of tumor and body weight in 108 cancer patients. Estimated mean GC values for the next 5 years and survival time did not differ significantly from those in healthy subjects (n=60). They were lower than in the US population which is likely to be due to a number of ethnic, hormonal and screening-related factors. GC tended to grow in RE+ tumor bearers, particularly at reproductive age, and in obese postmenopausal patients. Further study is expected to throw light on the relationships of GC, on the one hand, and certain hormono-metabolic characteristics and clinical course of breast cancer, on the other. This in turn may prove useful in designing therapeutic strategies and, in particular, administration of antisteroid and antimetabolic drugs for prophylaxis in groups at high risk.

Adult↗

PubMed2003

Tumor estrogen content and clinico-morphological and endocrine features of endometrial cancer.

OBJECTIVES: To compare estrogen concentrations in endometrial cancer tissue with those in macroscopically normal endometrium and with certain morphological characteristics of the tumor and endocrine parameters in patients. METHODS: The estradiol content was evaluated by radioimmunoassay after homogenization and extraction in 78 adenocarcinomas (61 from postmenopausal patients). RESULTS: Higher concentrations of estradiol in tumor tissue samples than in macroscopically normal endometrium were found in patients of both reproductive and postmenopausal age. This difference was the same in patients with either endometrial carcinoma type I or type II. No association between tumor steroid receptor levels, estradiol concentrations in blood serum, and timing of menopause with intratumoral estradiol contents was discovered. Estradiol concentrations in tumor tissues correlated positively with the clinical stage of disease and rate of tumor invasion (in patients with peripheric/lower type of fat topography), and negatively with tumor differentiation stage (in patients with central/upper type of fat topography) and the percentage of intact double-stranded DNA in normal endometrium. CONCLUSIONS: Tumor estrogen content in endometrial cancer has clinical significance that is modified in the presence of certain endocrine characteristics related to insulin resistance. The role of local estrogen production (aromatase activity) in this setting deserves special study.

Aged↗

PubMed2003

Mammary tumors in HER-2/NEU mice are characterized by low content of estrogen receptors-alpha and absence of progesterone receptors.

Transgenic mice carrying erbB2(HER-2)neu gene are characterized by high incidence of mammary adenocarcinoma. The content of estrogen receptor was no more than 10 fmol/mg protein in 8 of 14 studied tumors, while the content of progesterone receptors was even lower in all 14 studied tumors. Based on these data, we distinguish two subtypes of HER-2/neu-adenocarcinomas in mice: ER+,PR- and ER-,PR-, which can be used for the development of new approaches to the treatment of receptor-negative mammary gland tumors.

Adenocarcinoma↗

PubMed2003

Expression of estrogen receptors-beta and aromatase activity in primary mammary gland tumors.

Expression of estrogen receptors alpha and beta was studied by the PCR method in 22 primary receptor-positive or receptor-negative breast carcinomas obtained during surgical intervention from patients aged 41-77 years and activity of aromatase in the same specimens was evaluated by the formation of tritiated water from labeled androgen precursor. Expression of estrogen receptors alpha and beta was more often detected in receptor-positive tumors characterized by lower aromatase activity. The authors conclude that the intensity of local production of estrogens can be one of the regulators of their expression, limiting this expression in case of more active production of estrogen in the tumor. On the other hand, there were no differences in the expression of estrogen beta-receptor gene or in detection of this receptor by immunocytochemical method in primary tumors lacking one of these receptors, and hence, this form of estrogen receptors is less involved in induction of progesterone receptors than alpha-receptors.

Adult↗

PubMed2003

[Hormonal-metabolic status of cancer patients with late-onset menopause].

Late-onset of menopause is a marker of risk factor for neoplasia in the reproductive system and, conversely, anti-risk for certain non-infectious diseases, such as cardio-vascular disease or osteoporosis. We studied 118 postmenopausal patients with early endometrial and breast cancers. The investigation was particularly concerned with hormonal-metabolic status versus age at menopause age at. While a Quetelet index/age was irrelevant, blood cholesterol and insulin (120 min) concentrations and tumor estrogen/progesterone receptor ratios were relatively higher in the late-onset group ((52 yrs). This group showed a correlation with age at menopause while the other one--with its duration. Insulin/body weight ratios were higher in the late-onset group while LH/FSH--lower. Hence, patients of the same age but differing in age at menopause age at may show differences in hormonal-metabolic status as well. This feature may be significant in identifying both biological distinctions of associated tumors and their clinical course.

Age of Onset↗

PubMed2003

[Comparative characteristics of hormonal status in patients with receptor-negative cancers of the breast and of the endometrium].

2,429 breast cancer patients and 478 patients with endometrial carcinoma were examined. It was suggested that the absence of estrogen receptors (ER) and/or progesterone receptors (PR) should be accounted for by peculiar endocrine features (including those of reproductive function) of the patients' medical history and/or hormonal metabolic status (body weight, estrogenemia, insulinemia, etc.) at clinical detection of tumor. The differences between breast and endometrial cancer in receptor-negative (R-) incidence were related to age (decade of lifespan) and menstrual cycle. Indices describing hormone-metabolic status were used for identification of receptor-negative or receptor-positive status of tumor (reliability of 65-70% for breast cancer and 75-80%--endometrial carcinoma) when it was not feasible under laboratory conditions.

Adult↗

PubMed2003

[Switching off the estrogen effect and approaches to its correction].

Data are summarized on experimental means of induction of PSEE and its modification/prevention with the aim to achieve optimal ratio of estrogenic effects (as low as possible genotoxicity in combination with satisfactory and excessive hormonal action). Among studied agents were ethanol, tobacco smoke, irradiation, aging (as PSEE inductors) and carnosine, N-acetylcystein, vit. E and C, melatonin, swimming and antiestrogen ICI 182780 (as PSEE modificators).

Acetylcysteine↗

PubMed2002

Modification of the uterotropic effect produced by estrogens in aging rats.

We studied the influence of various methods for correction of age-related changes (administration of N-acetyl-L-cysteine, vitamins C and E, melatonin, and carnosine and swimming training) on the realization of estrogens effects in ovariectomized rats. The proliferation index in the endometrium decreased in 12-14-month-old control animals. The weight of the uterus, percentage of "comets", and average length of their tail in estradiol-treated rats far surpassed the corresponding parameters in control animals. Administration of melatonin and N-acetyl-L-cysteine and swimming training corrected these genotoxic abnormalities. Our results indicate that aging induces incomplete variant of the phenomenon for switching of estrogen's effects (increase in the severity of genotoxic damage without facilitation of the hormonal effect). These methods for correction of age-related changes have not only common, but also distinguishing characteristics compared to correction of changed induced by drinking of ethanol in various concentrations, whole body gamma-irradiation, and exposure to tobacco smoke.

Acetylcysteine↗

PubMed2001

Modification of uterotropic effect of estrogens by whole-body gamma-irradiation.

The effect of gamma-irradiation on the realization of the effects of estrogens was studied on rats treated with N-acetylcysteine, vitamins C and E, melatonin, and carnosine or subjected to forced swimming in a training mode. Irradiation (0.2 Gy) in combination with estrogens and without correction therapy induced genotoxic changes in the uterus, while irradiation in a higher dose (2 Gy) predominantly potentiated the hormonal effect of estrogens. Correction of the revealed abnormalities was achieved mainly with carnosine. The peculiarities of "estrogen toggle (re-targeting) effect" under the effect of gamma-irradiation and its elimination differed from those induced by ethanol intake or tobacco smoking, which is important for understanding the mechanisms of hormone-induced carcinogenesis.

Acetylcysteine↗