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Aims: This study was launched to identify the SHMT2 associated Human Cancer subtypes., Background: Cancer is the 2nd leading cause of death worldwide. Previous reports revealed the limited involvement of SHMT2 in human cancer. In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2., Objective: We aim to comprehensively analyze the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Earlier, limited knowledge exists in the medical literature regarding the involvement of Serine Hydroxymethyltransferase 2 (SHMT2) in human cancer., Methods: In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Pan-cancer transcriptional expression profiling of SHMT2 was done using UALCAN while further validation was performed using GENT2. For translational profiling of SHMT2, we utilized Human Protein Atlas (HPA) platform. Promoter methylation, genetic alteration, and copy number variations (CNVs) profiles were analyzed through MEXPRESS and cBioPortal. Survival analysis was carried out through Kaplan-Meier (KM) plotter platform. Pathway enrichment analysis of SHMT2 was performed using DAVID, while the gene-drug network was drawn through CTD and Cytoscape. Furthermore, in the tumor microenvironment, a correlation between tumor purity, CD8+ T immune cells infiltration, and SHMT2 expression was accessed using TIMER., Results: SHMT2 was found overexpressed in 24 different subtypes of human cancers and its overexpression was significantly associated with the reduced Overall survival (OS) and Relapse-free survival durations of Breast cancer (BRCA), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), and Lung adenocarcinoma (LUAD) patients. This implies that SHMT2 plays a significant role in the development and progression of these cancers. We further noticed that SHMT2 was also up-regulated in BRCA, KIRP, LIHC, and LUAD patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of SHMT2 enriched genes in five diverse pathways. Furthermore, we also explored some interesting correlations between SHMT2 expression and promoter methylation, genetic alterations, CNVs, tumor purity, and CD8+ T immune cell infiltrates., Conclusion: Our results suggested that overexpressed SHMT2 is correlated with the reduced OS and RFS of the BRCA, KIRP, LIHC, and LUAD patients and can be a potential diagnostic and prognostic biomarker for these cancers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The association between human papillomavirus (HPV) and human breast cancer (BC) has already been thoroughly studied worldwide with contradictory findings. Although the researchers have tried to minimize the conflict using statistical meta-analysis because of its shortcomings, there is still a need to evaluate the correlation between HPV and BC using any additional method., Objectives: This study was launched to investigate the correlation between HPV and BC through the application of Bradford Hill criteria postulates., Methods: Population-wide studies associating HPV with BC were searched using the PubMed database. Then, the information of HPV burden in BC, normal/benign samples was analyzed, and ultimately Bradford Hill criteria postulates were applied on the collected evidence to explore the relationship between HPV and BC. In addition, to make the outcomes more authentic, we also reviewed the methodologies of previous studies to address the propensity of false results., Results: After a careful evaluation of the obtained data against major Bradford Hill criteria postulates, it was noted that all these postulates, including strength, consistency, biological gradient, temporality, plausibility, experiment, specificity, and analogy were not fulfilled., Conclusion: The results of the present study have failed to establish a causal association between HPV and BC, but they did suggest HPV as a cause-effective agent or at least a co-participant in the pathogenesis of BC. Because of the weakness of association, particularly the lack of consistency between studies and the lack of effect specificity, more research into Bradford Hill criteria postulates is required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Breast carcinogenesis is a multidimensional disease that has resisted drug-related solutions to date because of heterogeneity, disorganized spatiotemporal behavior of signal transduction cascades, cell cycle checkpoints, cell transition, plasticity, and impaired pro-apoptotic response. These synchronized oncogenic events, including protein-protein interaction, transcriptional-regulatory, and signaling networks, trigger genomic and transcriptional disturbances in TRAIL-mediated signaling network neighborhoods. Therefore, tumor cells often acquire the ability to escape death by suppressing cell death pathways that normally function to eliminate damaged and harmful cells. This review describes the TRAIL-mediated cell death signaling pathways, the interactions between these pathways, and the ways in which these pathways are deregulated in breast cancer.

In malignant breast tissue cytosols (n = 14), significantly high levels of oestradiol (E2), testosterone and 5a-dihydrotestosterone (DHT) and sex hormone binding globulin (SHBG) were found as compared to breast tissue cytosols from normal women (n = 12) (p less than 0.001 for all parameters measured). In serum from the same patients and normal control groups no differences in these hormones or SHBG were detected, nor was relationship between serological and cytosolic levels observed. In the cytosol of the malignant group there was a significant correlation between testosterone and DHT, r = 0.98, p less than 0.001. This was also the case in the cytosol of normal breast tissue, r = 0.97, p less than 0.001. No such correlation between the two androgens was observed in the sera of either group. We hypothesise that the malignant breast is able to regulate its own hormonal milieu and that the nearly 8 times higher levels of intracellular SHBG compared to those in normal breast cytosol may be one the factors responsible for this accumulation of sex-steroids. In addition, SHBG due to its higher affinity for androgens than for E2 may shift the balance in favour of free oestrogens in malignant breast tissue.

Gestodene, a new synthetic progestogen, binds to progesterone receptor (PR) derived from normal breast, endometrium and both normal and diseased liver with an affinity 8-10 times higher than that of the natural ligand. PR in malignant breast could not be quantified on account of the binding of gestodene to oestrogen receptor (ER) in that tissue. Sucrose density ultracentrifugation using 3H-oestradiol and 3H-gestodene in normal and malignant breast demonstrated that the gestodene-ER complex in addition to exhibiting the 4S and 5S peaks showed an additional peak which sedimented at 2.9-3.15. Dissociation kinetics of gestodene from ER which was either heat-activated or molybdate-stabilised were comparable to the triphenylethylene class of antioestrogens in that the rate of dissociation, unlike that of oestradiol from ER, was unaffected by these treatments. The binding of ER-gestodene to DNA-cellulose was also investigated and was found to be approximately 30% less than that of ER-oestradiol.

Oestrogen receptor protein (ER) was detected in 9 of 11 samples of malignant breast tissue and 8 of 9 samples of normal breast tissue. Levels of cytosolic ER (ERc) in malignant breast were 21-1102 fmol mg-1 soluble protein (Kd 1.8 X 10(-9)-3.1 X 10(-8) mol l-1) and those of nucleosolic ER (ERn), 13-526 fmol mg-1 soluble protein (Kd 2.1 X 10(-9)-1.4 X 10(-8) mol l-1). In normal breast tissue ERc levels were 33-640 fmol mg-1 soluble protein (Kd 1.3 X 10(-10)-3.2 X 10(-9) mol l-1), ERn was detected in only 2 samples, 8 and 87 fmol mg-1 soluble protein with Kd 3.2 X 10(-9) and 1.4 X 10(-9) l mol-1 respectively. 17 alpha-ethinyl-13 beta-ethyl-17 beta-hydroxy-4,15-gonadiene-3-one (gestodene), a new synthetic progestogen displaced 3H-oestradiol (3H-E2) from both ERc and ERn in malignant tissue but not in normal breast, or these receptors from endometrial tissue. In competition studies gestodene was approximately 3 times more effective in displacing 3H-E2 from ERc and ERn in malignant breast tissue than the natural ligand. Quantitation of ER by gestodene were ERc, 12-1134 fmol gestodene bound mg-1 soluble protein (Kd 1 X 10(-9)-8.1 X 10(-9) mol l-1); ERn, 17-531 fmol gestodene bound mg-1 soluble protein (Kd 1.6 X 10(-9)-1.1 X 10(-8) mol l-1). L-13-ethyl-17 alpha-ethinyl, 17 beta-hydroxy-gonen-3-one (levonorgestrel) showed no binding to ER in malignant breast, normal breast or endometrial tissue. In circulation both gestodene and levonorgestrel displaced E2 from sex hormone binding globulin more than any of the androgens tested. These results suggest that gestodene is a progestogen with oestrogenic and/or antioestrogenic properties and provide strong evidence for differences in ER from malignant and normal breast tissue.

Over-expression of oestrogen and progesterone receptor (ER and PR respectively) has been reported in malignant breast disease but the techniques employed have been relatively insensitive and prone to underestimations. Using a highly sensitive microassay method, we have estimated ER (n = 39), PR (n = 32) and androgen receptor (AR) (n = 37) in cytosolic and nucleosolic fractions obtained from the same tissue samples. Induction of PR by oestrogen is a widely recognized phenomenon, and a relationship between PR and ER is to be expected. There is evidence that sex-steroids and their receptors act in concert and it is therefore surprising that AR has been poorly studied in malignant breast disease, despite indications that its presence increases hormone responsiveness. Our hypothesis is that, unlike the normal breast, in malignancy a possible deregulation of transcriptional control may lead to an over expression of all three classes of sex-steroid receptor. Using the microassay, we have tested this hypothesis and found not only a greater incidence of ER, AR and PR than previously reported in malignant breast disease, but considerably higher levels of these receptors. In addition, our findings demonstrate that these receptors tend to be expressed simultaneously rather than discretely, supporting the view that a deregulation of transcriptional control may account for the clinical and biological heterogeneity of the disease.

The binding of the synthetic progestogen, 17 alpha-ethinyl-13 beta-ethyl-17 beta-hydroxy-4,15-gonadiene-3-one (gestodene) to estrogen receptor (ER) in malignant breast disease is refractory to competition by excess amounts of estra-1,3,5 (10)-triene-3,17 beta-diol (estradiol, E2) or tamoxifen, whereas gestodene in excess amounts can reduce the E2 binding sites by 31-44% and increase the Ka 2-3 times. Given the close similarity of the number of binding sites measured by E2 or gestodene and the similarity of dissociation constants, we propose that in the already altered ER of the malignant human breast there is another binding site for gestodene which closely approximates in number and affinity the binding site for E2, and that gestodene itself is capable of bringing about a configurational change which greatly reduces the binding of E2 to ER without completely abolishing it.