Down-regulation of MSH3 and MSH6 genes in female breast cancer patients receiving taxane-based therapy

Abstract Background The DNA in each cell in our body is constantly in danger of becoming damaged. Most DNA damage gets repaired straight away via many different proteins encoded by DNA—repair genes. MSH3 and MSH6 are pivotal DNA repair genes maintaining human genome integrity. Dysregulated expression of such genes has its implications resulting in developing of adverse reactions in cancer breast patients receiving taxanes. Cancer chemotherapy with some of taxane class of agents are associated with significant neurotoxicity, arthralgias and myalgias that may offset the therapeutic benefits of taxane use. Our aim is to identify gene expression pattern of MSH3 and MSH6 DNA mismatch repair genes in female breast cancer patients who develop adverse reactions to taxane-based therapy. One hundred and five patients with histologically proven breast cancer who received paclitaxel (PTX) as a single agent or combination therapy have been enrolled along with a group of 50 females with benign breast lesions serving as controls.Gene expression studies of mismatch repair genes (MMR) genes; MSH3 and MSH6; have been performed by real-time PCR. Patients were divided into groups according to the determined type/grade of PTX-based toxicity and fold changes of both genes were estimated. Results In the present work both MMR genes showed significantly lower expression in all the studied patients compared to benign cases as a control group. Toxicity findings were encountered in 75.2% of the studied patient cohort. The most common observed type of toxicity was peripheral neuropathy (PN), 58.1% of the studied patients. Both MSH3 and MSH6 genes were significantly down-regulated in the presence of high grade PN toxicity ≥ 2 (p = 0.034 and 0.01); diarrhea toxicity (p = 0.02 and 0.008); dyspnea (p = 0.01 and 0.016) respectively and bone pain (p = 0.024 for MSH6 only). Conclusion Dysregulated expression of MMR GENES [MSH3and MSH6] can be implicated in paclitaxel—induced toxicity experienced by some cancer breast patients

CYP2C8 rs11572080 and CYP3A4 rs2740574 risk genotypes in paclitaxel-treated premenopausal breast cancer patients

Abstract Breast cancer (BC) is the most prevalent malignancy in women globally. At time of diagnosis, premenopausal BC is considered more aggressive and harder to treat than postmenopausal cases. Cytochrome P450 (CYP) enzymes are responsible for phase I of estrogen metabolism and thus, they are prominently involved in the pathogenesis of BC. Moreover, CYP subfamily 2C and 3A play a pivotal role in the metabolism of taxane anticancer agents. To understand genetic risk factors that may have a role in pre-menopausal BC we studied the genotypic variants of CYP2C8, rs11572080 and CYP3A4, rs2740574 in female BC patients on taxane-based therapy and their association with menopausal status. Our study comprised 105 female patients with histologically proven BC on paclitaxel-therapy. They were stratified into pre-menopausal (n = 52, 49.5%) and post-menopausal (n = 53, 50.5%) groups. Genotyping was done using TaqMan assays and employed on Quantstudio 12 K flex real-time platform. Significant increased frequencies of rs11572080 heterozygous CT genotype and variant T allele were established in pre-menopausal group compared to post-menopausal group (p = 0.023, 0.01, respectively). Moreover, logistic regression analysis revealed a significant association between rs11572080 CT genotype and premenopausal BC. However, regarding rs2740574, no significant differences in genotypes and allele frequencies between both groups were detected. We reported a significant association between CYP2C8 genotypic variants and premenopausal BC risk in Egyptian females. Further studies on larger sample sizes are still needed to evaluate its importance in early prediction of BC in young women and its effect on treatment outcome

Effect of weight loss program using prebiotics and probiotics on body composition, physique, and metabolic products: longitudinal intervention study

Abstract The relationship between gut microbiota and obesity has recently been an important subject for research as the gut microbiota is thought to affect body homeostasis including body weight and composition, intervening with pro and prebiotics is an intelligent possible way for obesity management. To evaluate the effect of hypo caloric adequate fiber regimen with probiotic supplementation and physical exercise, whether it will have a good impact on health, body composition, and physique among obese Egyptian women or has no significant effect. The enrolled 58 women, in this longitudinal follow-up intervention study; followed a weight loss eating regimen (prebiotic), including a low-carbohydrate adequate-fiber adequate-protein dietary pattern with decreased energy intake. They additionally received daily probiotic supplements in the form of yogurt and were instructed to exercise regularly for 3 months. Anthropometric measurements, body composition, laboratory investigations, and microbiota analysis were obtained before and after the 3 months weight loss program. Statistically highly significant differences in the anthropometry, body composition parameters: and obesity-related biomarkers (Leptin, ALT, and AST) between the pre and post-follow-up measurements at the end of the study as they were all decreased. The prebiotic and probiotic supplementation induced statistically highly significant alterations in the composition of the gut microbiota with increased relative abundance of Lactobacillus, Bifidobacteria, and Bacteroidetes and decreased relative abundance of Firmicutes and Firmicutes/Bacteroidetes Ratio. Hypo caloric adequate fiber regimen diet with probiotics positively impacts body composition and is effective for weight loss normalizing serum Leptin and AST