[Molecular mechanisms of resistance to tamoxifen].
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Animals↗
Biomedical subjects
L M Berstein
Publications and source records attributed to L M Berstein.
[Genetic polymorphism of steroid 17 alpha-hydroxylase/17,20-lyase (CYP17) and hyperinsulinemia in endometrial carcinoma].
Initiation and/or promotion of endometrial carcinoma is considered to be associated with estrogens and androgens (androstendione) excess as well as hyperinsulinemia and resistance to insulin. It is possible that certain polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to carcinoma susceptibility. In the current study, we compared the role of CYP17 biallelic MspA1) polymorphism in 114 endometrial carcinoma patients and 182 healthy women. According to our data, A2/A2 CYP17 genotype traditionally regarded as "unfavorable" was less frequent in cancer patients than in control which confirmed the results of two previous publications. For the first time, carriers of the genotype were shown to have relatively low levels of blood insulin and C-peptide. No significant difference was found between mean concentrations of testosterone, dehydroepiandrosterone sulfate and those of estradiol in the carriers of various CYP17 genotypes with endometrial cancer. Hence, CYP17 polymorphism which is represented by the "normal" A1/A1 genotype might be a factor of risk for endometrial carcinoma. Since this genetic variety may develop through an unconventional (nonsteroid) pathway, taking relevant preventive measures in high-risk groups should be recommended.
Biomarkers, Tumor↗
CYP19 gene polymorphism in endometrial cancer patients.
PURPOSE: Initiation/promotion of endometrial cancer is known to be associated with estrogenic influence. Therefore, it is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. METHODS: Here, we compared CYP19 (aromatase) gene polymorphism in 85 endometrial cancer patients and in 110 non-affected women. RESULTS: The genotypes containing the longest alleles (A6 and A7) of CYP19 were found to be over-represented in patients as compared to controls. In addition, these genotypes demonstrated a tendency to be associated with increased concentrations of estradiol and testosterone in postmenopausal patients. CONCLUSIONS: Thus, CYP19 polymorphism might be one of the genetic risk factors for endometrial cancer development.
Adult↗
The potential role of estrogen in aromatase regulation in the breast.
Aromatase is expressed in both normal and malignant breast tissues. Aromatase activity in the breast varies over a wide range. Our previous studies have demonstrated that in situ aromatization contributes to the estrogen content of breast tumors to a major extent. Consequently, alterations of aromatase activity could serve as a major determinant of tissue estradiol content. However, the mechanisms and extent of aromatase regulation in breast tissues have not been fully established. We have observed an inverse correlation between tumor aromatase activity and estrogen content in nude mice bearing xenografts of MCF-7 cells transfected with the aromatase gene. To investigate the potential role of estrogen in aromatase regulation in the breast, studies were carried out in an in vitro model. In this model, MCF-7 cells were cultured long term in estrogen-deprived medium and called by the acronym, LTED cells. We found that long-term estrogen deprivation enhanced aromatase activity by 3-4-fold when compared to the wild-type MCF-7 cells. Re-exposure of LTED cells to estrogen reduced aromatase activity to the levels of the wild-type MCF-7 cells. We also measured aromatase activity in 101 frozen breast carcinoma specimens and compared tumor aromatase activities in pre-menopausal patients versus post-menopausal patients and in post-menopausal patients with or without hormone replacement therapy (HRT). Although statistically not significant, there was a trend paralleling that observed in the in vitro studies. Aromatase activity was higher in breast cancer tissues from the patients with lower circulating estrogen levels. Our data suggest that estrogen may be involved in the regulation of aromatase activity in breast tissues.
Animals↗
CYP17 polymorphism in the groups of distinct breast cancer susceptibility: comparison of patients with the bilateral disease vs. monolateral breast cancer patients vs. middle-aged female controls vs. elderly tumor-free women.
The CYP17 gene encodes an enzyme involved in several critical steps of steroidogenesis. The promoter region of the CYP17 displays a single-nucleotide polymorphism, which is suspected to modulate the expression of the gene and thus may contribute in the interindividual variations of hormonal background. In agreement with this functional hypothesis, the MspA1+ allele (designated as A2) of the CYP17 was shown to render an increased risk of breast cancer (BC). However, the latter observation was disputed by a series of negative reports. Here, we re-evaluated the role of CYP17 MspA1 polymorphism in the BC susceptibility, using a non-traditional design of a case-control study. In addition to randomly selected 183 BC patients and 107 female middle-aged donors, we examined the groups with apparently extreme characteristics of either BC risk or BC resistance, namely the 57 bilateral breast cancer (biBC) patients and 75 elderly (>/=75 years old) tumor-free women. Neither BC nor biBC patients showed increased prevalence of 'unfavorable' A2 allele as compared with the non-affected cohorts. Moreover, the A2 variant was not significantly associated with the tumor size, nodal involvement and menopausal status in the patients either with the monolateral or bilateral disease. Thus, our data argue against the earlier reported role of the CYP17 in BC predisposition and progression. In addition, usual distribution of the CYP17 alleles in the elderly group indicates a neutral effect of this polymorphism on the longevity in females.
Aged↗
Catecholestrogens excretion in smoking and non-smoking postmenopausal women receiving estrogen replacement therapy.
Estrogens are involved in the etiology of breast cancer. Their blastomogenic influence may be partly realized through their conversion into catecholestrogens, rate of which may be modified by smoking. The risk of having breast cancer diagnosed can increase in women using estrogen replacement therapy (ERT). The principal aim of this investigation was to compare the excretion of classical estrogens and catecholestrogens in smoking and non-smoking postmenopausal women receiving Progynova (estradiol valerate, 2 mg/day, 1 month). Total 16 women were studied before and after treatment. Urinary estrogen profile method based on isotope dilution capillary gas chromatography-mass spectrometry was used. Before ERT, significantly lower excretion of 16-epiestriol and 4-hydroxyestrone (4-OHE1) and lower ratio of 4-OHE1/E1 were revealed in smokers. After ERT, much higher excretion of 2-OHE1, and 4-hydroxyestradiol (4-OHE2), higher ratios of 2-OHE1/E1 and 4-OHE1/E1 and lower ratio of 2-methoxyestrone/2-OHE1 were discovered in smokers as compared to non-smoking women. In conclusion only combination of ERT + smoking and not smoking itself leads to the specific prevalence of catecholestrogens (2-OH- and carcinogenic and DNA-damaging 4-OH-metabolites) that may increase risk of genotoxic variant of hormone-induced breast carcinogenesis without influence on the total morbidity.
Breast Neoplasms↗
Prevention of spontaneous and chemically induced carcinogenesis using activated carbon fiber adsorbent. III. Inhibitory effect of the activated carbon fiber adsorbent 'Aqualen' on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats.
Two-month-old outbred female LIO rats were exposed weekly to 15 (experiment I, groups 1, 2 and 3) or to 5 (experiment II, groups 4, 5 and 6) subcutaneous injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg of body weight. From the day of the first injection of the carcinogen, the rats from groups 2, 3, 5 and 6 were given Aqualen in their diet. In both experiments rats were fed Aqualen five times per week together with lab chow at the daily dose of 0.1 g/kg (groups 2 and 5) or 1.0 g/kg (groups 3 and 6) of body weight. Additionally, other rats were not exposed to the carcinogen and served as an intact control (group 7) or were given Aqualen with the diet at the daily dose of 0.1 g/kg (group 8) or 1.0 g/kg (group 9). These experiments were finalized 6 months after the first injection of DMH. In experiments I and II, the majority of tumors were localized in the descending colon. Tumors of the small intestines developed only in rats from experiment I. The total incidence of colon tumors as well as tumors in different parts of the colon and the mean number of tumors per rat were much higher in rats from all groups in experiment I than in the rats from experiment II. In experiment I supplementation of Aqualen to the diet was followed by a decrease in the incidence of tumors in the ascending colon and by a decrease in the number of tumors per rat in both ascending and descending colons regardless of the dose of the enterosorbent. In experiment II the effect of Aqualen was stronger than in experiment I -- the enterosorbent decreased both the tumor incidence and the multiplicity in the total colon, its ascending and descending parts and in the rectum. In experiments I and II the percentage of small colon tumors among rats exposed to Aqualen (groups 2, 3, 5 and 6) was higher than that of the controls (groups 1 and 4). Most of detected intestinal tumors were classified as adenocarcinomas. The level of tumor differentiation was higher in rats exposed to Aqualen. There were no pathological changes observed in rats exposed to Aqualen without DMH. Carcinogen treatment resulted in an increase of serum glucose and cholesterol levels whereas Aqualen normalized these changes. Thus, our results demonstrate the inhibitory effect of activated carbon fiber adsorbent Aqualen on intestinal carcinogenesis in rats.
1,2-Dimethylhydrazine↗
Study of tobacco smoke influence on content of estrogens and DNA flow cytometry data in uterine tissue of rats of different age.
Female rats aged 2.5-3 months ("young") and 6 months ("adult") were or were not exposed to the influence of tobacco smoke (mainstream cigarette smoke, 2 hrs/day during 3 weeks or 3 months). Treatment with tobacco smoke did not induce any changes in uterine weight or estrous cycle but led to the decrease of estradiol (E2) concentration in uterine tissue (especially in adult rats or in young rats after 3 months of experiment). No signs of aneuploidy were found in uteruses of animals-"smokers" though proliferation index and percentage of cells in S-phase were increased (according to flow cytometry data) by 3 weeks and decreased by 3 months of experiment. The data obtained support previously made assumption pointing to phasic character of changes in reproductive system under the influence of tobacco smoke and may be used for further confirmation of the concept explaining the role of smoking in the shift of hormonal (estrogen-induced) carcinogenesis type from promotional to genotoxic one.
Aging↗
[Polymorphism of the genes of steroidogenesis and risk of malignant tumor development].
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Animals↗
[Hormonal metabolic status in breast cancer patients after conservative surgery: comparison with known prognostic criteria].
Body weight, body mass index, body fat, lean body mass, blood-glucose, cholesterol, HDL-cholesterol, triglyceride, beta-lipoproteins, insulin, gonadotropin, estradiol, testosterone, SHBG, T3, T4 and TSH levels as well as estradiol and progesterone receptor levels in excised tumor were studied in 40 patients with breast cancer prior to conservative treatment. Said anthropometric, metabolic and hormonal parameters were compared with the index of lymphocytic infiltration of tumor selected as a prognostic factor. A significant correlation between high lymphocytic infiltration (2.5 points), low body mass and fat was identified. Also, smoking contributed to loss of body mass and fat; however, it caused lymphocytic infiltration to rise. Moderate body mass, relatively low fat level and positive receptor status are among factors of good prognosis in breast cancer of early stages.
Adipose Tissue↗
[Aromatase gene expression and its modifying factors in breast tumor tissue].
Aromatase (CYP 19) gene expression was studied in 70 breast tumors. When RNA-dot-blot or rt-polymerase chain reaction were used expression frequency was 60.4 and 91.7%, respectively. An analysis of individual variants of non-coding exon of aromatase gene confirmed that, unlike normal mammary tissue, tumor switched from activation of exon I.4 ("sensitive" to glucocorticoids) to exons II ("sensitive" to cAMP) or I.3. This difference was relatively somewhat more pronounced in the Russian material. Direct correlation between aromatase enzymatic activity and expression of exons II and I.3 in tumor tissue appeared more significant than that of aromatase gene coding site. An evaluation of the expression of adenylate cyclase G-protein alpha-subunit genes established an inverse correlation between expression of Gi2a and exon I.3. Breast tumors with elevated basal aromatase activity were more sensitive to aromatase inhibitors (letrozole, 4-OHA) in vitro although no relationship between use of CYP19 (aromatase) 5' exon variant and in vitro inhibition of aromatase was detected. A correlation was observed between expression of aromatase gene and variants of its 5' exon, on the one hand, and age, tumor grade, steroid receptor presence and tumor lymphocytic infiltration, on the other. To summarize, local estrogen production in breast tumor tissue is regulated by a wide range of factors expression both aromatase gene influencing and its enzymatic activity, thus providing leverage on both.
Adult↗
Ability of lymphocytes infiltrating breast-cancer tissue to convert androstenedione.
Lymphocytes were isolated from 43 surgical samples of breast cancer after tumor enzyme digestion and Ficoll/Verographine procedure. In all, 23 specimens from lymphocytic-tissue infiltrates were analyzed (in some cases, material from 2 or 3 patients was combined). The ability of tumor-infiltrating lymphocytes (TIL) to convert androstenedione was demonstrated, as evaluated by hard-water release from the androgenic precursor 3H-1beta-androstenedione. In material obtained from menopausal women this ability was higher than in the women of reproductive age. A positive correlation was revealed between the level of androstenedione conversion in TIL and aromatase activity in tumor tissue, while no correlation was shown between androstenedione conversion in TIL and percentage of tumor cells in lymphocytic suspension. The data obtained suggest that factors secreted by a neoplasm are able to induce aromatase gene expression in TIL.
Androstenedione↗
Influence of tobacco smoke on DNA unwinding and uterotrophic effect of estrogens in rats.
Experiments with a duration of either 3 weeks or 3 months were conducted on female rats with initial body weights of 140-170 g. All animals were divided into four groups, i.e. control, tobacco smoke (TS, a whole-body exposure to the mainstream cigarette smoke), estrogen (EG, diethylstilbestrol) and TS + EG. Injection of EG started on the day of bilateral ovariectomy which was performed in all animals 11 days before the end of the experiment. In short 3-week experiments TS weakly stimulated uterine wet weight and in combination with EG significantly increased the percentage of intact non-unwound DNA in uterine tissue (stimulation stage). In the longer 3-month experiments TS decreased a specific hormonal effect of EG, i.e. the ability to induce progesterone receptors in uterine tissue, and did not interfere with the DNA-damaging effect of diethylstilbestrol. The conclusion was made that different phases exist in hormonal and genotoxic responses to the combined effect of tobacco smoke and estrogens, which may be related to the mechanisms and types of hormonal carcinogenesis.
Animals↗
Macrophages, estrogen and the microenvironment of breast cancer.
Estrogen is a major mitogenic stimulus to established breast cancer. Estrogen sources include ovarian, extraglandular sites and breast tissue. Which source primarily maintains benign and breast cancer tissue estrogen concentrations remains unclear. While macrophages may comprise up to 50% of the mass of breast carcinomas, previous studies neglected to study them as possible sources of estrogen. We present evidence that breast macrophages constitute an in situ source of estradiol and that the amount produced is sufficient to mediate cellular proliferation. We utilized immunohistochemistry and RT-PCR to study cell-specific aromatase expression in (i) 29 breast biopsies, (ii) human monocytes/macrophages and (iii) a myeloid cell line (THP-1) capable of differentiating into macrophages. Use of a breast cancer cell line (MCF-7) provided biologic confirmation of the role of aromatization in cell proliferation. We demonstrated considerable amounts of immunoreactive-aromatase (irARO) in breast tissue macrophages and a positive correlation between the proportion of irARO present in macrophages and lesion severity. Using in vitro techniques, we demonstrated that monocytes and THP-1 cells require differentiation into macrophages to produce aromatase in amounts approaching placental levels. The amount of estrogen produced by THP-1 cells stimulated MCF-7 cells to proliferate, an effect blocked by aromatase inhibitors. Estrogen production by macrophages in breast tissue appears sufficient to stimulate the proliferation of adjacent epithelial cells and to autoregulate cytokine production. These findings represent a new dimension of cellular regulation in breast tissue with major biologic implications, amenable to pharmacological manipulation.
Antineoplastic Agents↗
[Aromatase activity and its gene expression in tumor tissue of smokers and non-smokers with breast cancer].
Tissue was sampled from 121 tumors of the breast. The activity of aromatase (estrogen synthetase) was assessed by radiobiochemical means in 61 cases; gene expression was evaluated with the aid of polymerase chain reaction in 14 and the same--by the dot-blot procedure in 46 patients. Inveterate smokers (15 years and more) made up 16.5%. The smokers revealed a distinct tendency towards aromatase activity decreasing in tumor tissue (chiefly in menopausal patients) as well as lower intensity of aromatase gene expression assessed in terms of polymerase chain reaction. Alongside with other evidence, our finding point to long-term-smoking-related sensitivity of intratissular estrogen synthesis being higher than in general circulation. It also demonstrated local aromatization inhibition in tumor tissue, the latter being a possible mechanism which causes tumor tissue hormone sensitivity to change in smokers and affects course of disease.
Adult↗
[Multifactorial model of estrogen synthesis in tumor tissue of breast cancer].
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Animals↗
[Correlation between tumor tissue aromatase, histological pattern and reproductive status in patients with breast cancer].
Aromatase levels were measured in tumor tissue vis-a-vis clinico-morphological patterns of tumor, menopausal status and sex hormone concentration in blood in 50 patients with breast tumors. The test was based on heavy water release from 1 beta-3H-androstenedione. Direct correlation was established between aromatase concentration, on the one hand, and tumor size, cell differentiation status and blood-testosterone on the other. The data point to the role of aromatase concentration in situ during breast tumor genesis, its dependence on hormonal environment of tumor and its presence in breast tumor cells.
Adult↗
[Blood insulin and insulin sensitivity in breast cancer patients of various ages: the effect of smoking].
Blood-glucose and insulin were assayed by administering 40 g/sq.m glucose (per os) and 0.08 unit/kg body weight in 113 patients with early-stage breast tumors (glucose-tolerance test) and in 62 patients (insulin-sensitivity test). Sensitivity to insulin was assessed versus age, reproductive status, body size and smoker/non-smoker status. A direct correlation between high level of reactive insulinemia and obesity and an inverse one--between sensitivity to insulin and age were established on the basis of insulin test data and the insulin resistance factor. Smokers showed, on the average, lowered basal insulin levels and increased sensitivity to insulin (depending on age and number of cigarettes consumed). Smoking was found to influence prolactin reaction to hypoglycemia and to upset the correlation between age and progesterone receptor concentration in tumor which may account for certain peculiarities of the course of the disease in smokers with breast tumors.
Adult↗