Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer

Copyright © 2007 by The Federation of American Societies for Experimental BiologyThere is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT. We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.Stephen N. Birrell, Lisa M. Butler, Jonathan M. Harris, Grant Buchanan and Wayne D. Tille

Association of repeat polymorphisms in the estrogen receptors alpha, beta (ESR1, ESR2) and androgen receptor (AR) genes with the occurrence of breast cancer

Genetic variation in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to play a role in breast cancer. To determine the possible contribution of genetic variation in the ESR1 (ER-alpha), ESR2 (ER-beta) and AR genes in breast cancer risk the - 1174(TA)(7-27), c. 1092 + 3607(CA)(10-26) and c. 172(CAG)(6-40) repeat variants were studied in a case-control study of 79 women with sporadic breast cancer and 155 controls. No significant difference was observed in the frequency distribution of -1174(TA)(7-27) in the ESR1 gene between patients and controls, while a significant difference was observed for repeat polymorphisms c. 1092 + 3607(CA)(10-26) in the ESR2 gene and c. 172(CAG)(6-40) in the AR gene (p <= 0.0001). A significantly decreased odds ratio (OR) for breast cancer risk was observed in individuals having the LL and the SL genotypes for both the ESR2 (OR = 0.010, 95% CI 0.003-0.036, p<0.001; OR = 0.013, 95% CI 0.004-0.040, p<0.0001, respectively) and the AR gene (OR = 0.040, 95% CI 0.011-0.138, p<0.0001; OR = 0.189, 95% CI 0.10-0.359,p<0.0001, respectively), compared to SS genotype. The protective effect of these genotypes remained evident even after adjustment for various risk factors (BMI, age, age at menarche and menopause, family history). In conclusion, an association for breast cancer risk between short (SS) alleles for the repeat variants of the ESR2 and AR genes was found in women of Greek descent. (C) 2007 Elsevier Ltd. All rights reserved

A Novel 8-Predictors Signature to Predict Complicated Disease Course in Pediatric-onset Crohn’s Disease: A Population-based Study

International audienceBackground The identification of patients at high risk of a disabling disease course would be invaluable in guiding initial therapy in Crohn’s disease (CD). Our objective was to evaluate a combination of clinical, serological, and genetic factors to predict complicated disease course in pediatric-onset CD. Methods Data for pediatric-onset CD patients, diagnosed before 17 years of age between 1988 and 2004 and followed more than 5 years, were extracted from the population-based EPIMAD registry. The main outcome was defined by the occurrence of complicated behavior (stricturing or penetrating) and/or intestinal resection within the 5 years following diagnosis. Lasso logistic regression models were used to build a predictive model based on clinical data at diagnosis, serological data (ASCA, pANCA, anti-OmpC, anti-Cbir1, anti-Fla2, anti-Flax), and 369 candidate single nucleotide polymorphisms. Results In total, 156 children with an inflammatory (B1) disease at diagnosis were included. Among them, 35% (n = 54) progressed to a complicated behavior or an intestinal resection within the 5 years following diagnosis. The best predictive model (PREDICT-EPIMAD) included the location at diagnosis, pANCA, and 6 single nucleotide polymorphisms. This model showed good discrimination and good calibration, with an area under the curve of 0.80 after correction for optimism bias (sensitivity, 79%, specificity, 74%, positive predictive value, 61%, negative predictive value, 87%). Decision curve analysis confirmed the clinical utility of the model. Conclusions A combination of clinical, serotypic, and genotypic variables can predict disease progression in this population-based pediatric-onset CD cohort. Independent validation is needed before it can be used in clinical practice