High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation.

Autoantibodies to estrogen receptors and their involvement in autoimmune diseases and cancer.

The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several diseases including some cancers, most notably breast cancer, and autoimmune disorders. Estrogenic signal is transferred via estrogen receptors (ER) which have dual localization, predominantly intracellular but also in plasma membrane. The discovery of membrane-associated ER (mER) has greatly expanded our understanding of estrogen action; upon ligand binding, mER rapidly activate different signaling pathways inducing downstream transcription factors.

Genetic polymorphisms potentially associated with response to metformin in postmenopausal diabetics suffering and not suffering with cancer.

Metformin is a well-known antidiabetic medication, which, besides diabetes, may be involved into modulation of other age-related pathologies, including cancer. The study concerns 12 gene polymorphisms divided into 2 groups consisting of 6 genes each. The first group was composed from so-called "standard" (S) polymorphisms, for which the connection with metabolic response to metformin is already established.

Drug delivery approaches for ovarian cancer therapy.

Tumor-specific drug delivery represents a challenging issue that restricts the clinical applications of many advanced anticancer therapeutics. Ovarian cancer exhibits a quite specific pattern of dissemination: it spreads primarily within the peritoneal cavity, providing a possibility of locoregional, intraperitoneal drug administration. Considering this unique aspect of ovarian cancer biology, this chapter provides a short review of most promising approaches for therapeutic delivery of genetic drugs.

In vivo and in vitro properties of ovarian cancer cells.

Specific biological properties of ovarian cancer cells can be modeled and studied using in vitro experiments. Any experimental setting can closely reflect some aspects of the native conditions; however, parameters that differ from in vivo aspects must be considered. Familiarity with existing and well-established, as well as new, cell culture techniques provides a basis for correct experimental design and production of reliable scientific results.

Energy metabolism and changes in cellular composition in ovarian cancer.

Ovarian cancer possesses metabolic properties typical for any malignancy as well as some specific characteristics. Most of the methodological approach to study metabolism and molecular composition of the living cells are suitable for ovarian cancer research, however, might require minor modifications. The chapter reviews various laboratory techniques adapted to study ovarian cancer.

RNA networks in ovarian cancer.

Development of ovarian cancer is known to be associated with alterations in the expression of cellular RNAs. Most of the clinical and biological characteristics of ovarian cancer have been correlated with significant changes in the expression of a subset of genes. Over the last few years, considerable resources have been focused on understanding the complex structure and function of noncoding RNAs, and this paradigm is also applicable to ovarian cancer research.

Cancer endocrinology through own experience: areas for further thought and development. Interview by Natasha Galukande.

Lev Berstein speaks to Natasha Galukande, Assistant Commissioning Editor. Lev Berstein is Chief of Laboratory of Oncoendocrinology at the Petrov Research Institute of Oncology, St Petersburg, Russia. His main scientific interests include mechanisms of hormonal carcinogenesis, studying risk factors of hormone-associated tumors, and new approaches for prevention and treatment of the latter.

High baby birth weight and risk of hormone-associated cancer in mothers: the cancer-cardiovascular disease dichotomy and its possible causes.

The idea of intrauterine or fetal factors being the cause of several prevalent noninfectious diseases in adults has recently gained the status of an axiom. One of the most thoroughly studied predictors is birth weight (BW). Although many published studies point at relations between BW and later adult morbidity or mortality, much less attention is paid to associations between baby BW and maternal morbidity.

Selection of optimal combinations of target genes for therapeutic multi-gene silencing based on miRNA co-regulation.

Therapeutic gene silencing is a promising approach for treatment of cancer. Despite substantial efforts, however, only few such therapeutic methods have been clinically tested. The heterogeneity in gene expression profiles among malignant tissues and the dynamic control of gene expression in individual tumors makes identifying universal and effective targets a challenge.

Cancer and heterogeneity of obesity: a potential contribution of brown fat.

Obesity has lately been drawing additional attention as a potential cancer risk and, with some exceptions as a prognostic factor. As obesity is a complex issue characterized by different variants, mechanisms and manifestations, its role in cancer development is also a complex problem exceeding the basic fact of the fat content rising above certain limits. Therefore, in the present paper obesity is viewed as a heterogeneous entity, which has distinct connections with cancer pathogenesis.

Dark and light side of obesity: mortality of metabolically healthy obese people.

Evaluation of: Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J.

Metformin in obesity, cancer and aging: addressing controversies.

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender- and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.

Familial diabetes is associated with reduced risk of cancer in diabetic patients: a possible role for metformin.

Type 2 diabetes mellitus (DM2) is a risk factor of a number of malignancies. Therefore, it is important to identify factors linking DM2 and cancer within family units and how current treatment regimens influence the development of cancer in DM2 patients. The present case-controlled study was designed to assess DM2 prevalence among parents or siblings of (a) cancer patients who did not have diabetes (n = 77; age 59.

Isolated and combined action of tamoxifen and metformin in wild-type, tamoxifen-resistant, and estrogen-deprived MCF-7 cells.

Resistance to tamoxifen (TAM) and aromatase inhibitors represents a major drawback to the treatment of hormone-dependent breast cancer, and strategies to overcome this problem are urgently needed. The anti-diabetic biguanide metformin (MF) exerts pleiotropic effects which could enhance the effectiveness of available hormonal therapies. This study modeled several aspects of hormonal therapy in women and examined the effectiveness of MF under those conditions.

Metformin, insulin, breast cancer and more..

EVALUATION OF: Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG: Insulin-lowering effects of metformin in women with early breast cancer. Clin. Breast Cancer 8(6), 501-505 (2008).

Role of endocrine-genotoxic switchings in cancer and other human diseases: basic triad.

Cancer is one of the leading causes of human death and belongs to the group of main chronic noncommunicable diseases (NCD). Certain specific features ofNCD have raised the concept of 'normal' and 'successful' aging. The apparent paradox of simultaneous increase with aging of the diseases connected with estrogen deficiency as well as with estrogenic excess can be explained by the existence of the phenomenon of the switching of estrogen effects.

Signs of proinflammatory/genotoxic switch (adipogenotoxicosis) in mammary fat of breast cancer patients: role of menopausal status, estrogens and hyperglycemia.

The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such "adipose milieu" is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or "adipogenotoxicosis." We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.

The phenomenon of the switching of estrogen effects and joker function of glucose: similarities and relation to age-associated pathology and approaches to correction.

Estrogens and glucose are characterized by a myriad of functions that can be reduced to a small number of principal actions. In aging there is a simultaneous increase in the prevalence of diseases connected with estrogen deficiency as well as with estrogenic excess and associated with the phenomenon of the switching of estrogen effects (PSEE). Estrogens possess hormonal and genotoxic properties.

Aromatase and comparative response to its inhibitors in two types of endometrial cancer.

Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p=0.

Clinical usage of hypolipidemic and antidiabetic drugs in the prevention and treatment of cancer.

Factors predisposing hormone-dependent tissues to the development of tumors coincide, at least partly, with hormonal-metabolic promoters (like insulin resistance, glucose intolerance, visceral obesity, etc.) of other main non-communicable diseases. This important knowledge poses the question of whether the same approach which is applied for prevention/treatment of a metabolic syndrome and the associated endocrine disorders might also be used in preventive and therapeutic oncology.

CYP19 gene expression and aromatase activity in endometrial cancer tissue: importance of the type of the disease.

Aromatase (CYP19) activity in malignant endometrium presents local mechanism with potential ability to support tumor growth. The data on interrelation between activity of this enzyme and its mRNA signal in endometrial cancer (EC) tissue are very scarce and inconclusive. To correct this gap we studied aromatase activity and gene expression totally in 19 samples of EC (17 of them -- from postmenopausal women) collected during surgery.

CYP17 and CYP19 genetic polymorphisms in endometrial cancer: association with intratumoral aromatase activity.

Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Allelic polymorphisms of the genes involved in steroidogenesis/steroid metabolism may contribute to EC susceptibility. It is important to know endocrine mechanisms by which such susceptibility is acquired.

Long-term exposure to tamoxifen induces hypersensitivity to estradiol.

In women with hormone-dependent breast cancer, tamoxifen (TAM) frequently induces tumor regression, but regrowth occurs with continuation of antiestrogen therapy. Studies of breast xenografts in nude mice suggest that this secondary resistance to TAM may reflect the development of enhanced sensitivity to the estrogenic properties of TAM. In the current study, we examined the hypothesis that TAM could also induce a state of hypersensitivity to estradiol (E(2)) itself.