Direct DNA binding by BRCA1 on ß-hCG promoter and its clinical implications.

Objective: The role of ß-hCG in breast cancer is largely unknown, this study aims to analyse the gene expression and clinical implications of ß-hCG and its isoforms in various cancers focussing particularly in Breast Invasive Carcinoma (BRCA). A mechanistic approach deciphering the transcriptional regulation of ß-hCG by BRCA1 was also explored. Methods: Data from various comprehensive gene expression platforms like UALCAN, GEPIA2, GENT2, TIMER2, LinkedOmics, and STRING were used to analyse the expression of ß-hCG and its clinical implications; Immunohistochemistry and ELISA for ß-hCG expression analysis from human breast cancer patients; Electrophoretic mobility shift assay (EMSA) to analyse the direct binding of BRCA1 on ß-hCG; Immunoblotting and Luciferase assay to understand the regulation of ß-hCG by p53 were performed. Results: Results from UALCAN and GENT2 gene expression cancer database revealed that TNBC subtypes and high-grade metaplastic carcinoma shows elevated expression of ß-hCG and infiltration of various immune cells were also identified in BRCA by TIMER2. It was observed that most of the isoforms of ß-hCG (CGB) are upregulated in breast cancers irrespective of hormonal status when BRCA1 gene is mutated according to TIMER2. Similar results were observed with Lymphoid neoplasm diffuse large B-cell lymphoma (LGG) and DLBC (Brain lower grade glioma) when BRCA1 is mutated. These results correlate with our earlier reports indicating expression of ß-hCG in BRCA1 defective condition. We have also identified direct binding of BRCA1 on ß-hCG promoter. Conclusion: All these findings demonstrate the importance of ß-hCG as a potential target in BRCA1-deficient carcinomas.

Xenoestrogen and Its Interaction with Human Genes and Cellular Proteins: An In-Silico Study.

BACKGROUND: Breast cancer represents one of the leading causes of death worldwide. Apart from genetic factors, the sex hormone estrogen plays a pivotal role in breast cancer development. We are exposed to a plethora of estrogen mimics on a daily basis via various routes. Nevertheless, how xenoestrogens, the exogenous estrogen mimics, modulate cancer-associated signaling pathways and interact with specific genes is still underexplored. Hence, this study aims to explore the direct or indirect binding partners of xenoestrogens and their expression upon exposure to these estrogenic compounds. METHODS: The collection of genes linked to the xenoestrogens Octylphenol, Nonylphenol, Bisphenol-A, and 2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane were gathered from the Comparative Toxicogenomics Database. Venny 2.1 was utilized to pinpoint the genes shared by these xenoestrogens. Subsequently, the shared genes underwent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery bioinformatics resource. A xenoestrogen-protein interaction network was constructed using Search Tool for Interactions of Chemicals. The expressions of common genes were studied with the microarray dataset GSE5200 from the Gene Expression Omnibus database. Also, the expression of a common gene set within different breast cancer subtypes was identified using the University of California, Santa Cruz Xena. RESULTS: The genes linked to xenoestrogens were identified, and 13 genes were found to interact with all four xenoestrogens. Through DAVID analysis, the genes chosen are found to be enriched for various functions and pathways, including pathways in cancer, chemical carcinogenesis-receptor activation, and estrogen signaling pathways. The results of the Comparative Toxicogenomics Database and the chemical-protein interaction network derived from STITCH were similar. Microarray data analysis showed significantly high expression of all 13 genes in another study, with Bisphenol-A and Nonylphenol treated MCF-7 cells, most of the genes are expressed in luminal A or basal breast cancer subtype. CONCLUSION: In summary, the genes associated with the four xenoestrogens were mostly linked to pathways related to tumorigenesis, and the expression of these genes was found to be higher in breast cancer.

Ornamental roses for conservation of leafcutter bee pollinators.

Pollinator conservation is a global priority. Efforts are taken to restore pollinators by improving flower resources, a crucial driver of pollinator diversity and population growth. It helped gardening and landscaping supply chains, which introduced lists of bee-friendly plants and bee hotels, yet, desirable results seem distant. One shortcoming of the present schemes is that they lack a cohesive planning for nesting opportunities and nesting provisions for wild solitary bees, the crucial pollinators of crop and wild plants. We tested whether the world's popular ornamental plant, rose (Rosa chinensis Jacq.)-a hitherto unlisted bee-friendly plant-can aid in conserving leafcutter bees, which require fresh leaves for constructing nest cells. We surveyed 2360 rose plants in 136 sites in rural and urban places and lowlands and highlands of south (8°N-12°N) and northeastern India (26°N-27°N) for the characteristic notches the bees leave on foraged leaves. We reared brood constructed with rose and non-rose leaves to examine the brood success rate. About a quarter of all the roses surveyed had the notches of leafcutter bees on the leaves. However, the proportion of cut roses varied considerably among sites. Bees used roses much higher in urban areas and lowlands than in rural areas and highlands. The selection of plants was negatively associated with pesticide application. The brood success rate was 100% for the brood that was constructed by the leaves of rose and non-rose plants. Rose flowers do not support bees, but rose leaves indeed do. We recommend rose plants in leafcutter bee conservation and restoration schemes, particularly in urban environment.

Modulation of BRCA1 mediated DNA damage repair by deregulated ER-α signaling in breast cancers.

BRCA1 mutation carriers have a greater risk of developing cancers in hormone-responsive tissues like breasts and ovaries. However, this tissue-specific incidence of BRCA1 related cancers remains elusive. The majority of the BRCA1 mutated breast cancers exhibit typical histopathological features of high-grade tumors, with basal epithelial phenotype, classified as triple-negative molecular subtype and have a higher percentage of DNA damage and chromosomal abnormality. Though there are many studies relating BRCA1 with ER-α (Estrogen receptor-α), it has not been reported whether E2 (Estrogen) -ER-α signaling can modulate the DNA repair activities of BRCA1. The present study analyzes whether deregulation of ER-α signaling, arising as a result of E2/ER-α deficiency, could impact the BRCA1 dependent DDR (DNA Damage Response) pathways, predominantly those of DNA-DSB (Double Strand break) repair and oxidative damage response. We demonstrate that E2/E2-stimulated ER-α can augment BRCA1 mediated high fidelity repairs like HRR (Homologous Recombination Repair) and BER (Base Excision Repair) in breast cancer cells. Conversely, a condition of ER-α deficiency itself or any interruption in ligand-dependent ER-α transactivation resulted in delayed DNA damage repair, leading to persistent activation of γH2AX and retention of unrepaired DNA lesions, thereby triggering tumor progression. ER-α deficiency not only limited the HRR in cells but also facilitated the DSB repair through error prone pathways like NHEJ (Non Homologous End Joining). ER-α deficiency associated persistence of DNA lesions and reduced expression of DDR proteins were validated in human mammary tumors.

Deregulated estrogen receptor signaling and DNA damage response in breast tumorigenesis.

Carriers of BRCA1 mutations have a higher chance of developing cancers in hormone-responsive tissues like the breast, ovary and prostate, compared to other tissues. These tumors generally exhibit basal-like characters and do not express estrogen receptor (ER) or progesterone receptor (PR). Intriguingly, BRCA1 mutated breast cancers have a less favorable clinical outcome, as they will not respond to hormone therapy. BRCA1 has been reported to exhibit ligand dependent and independent transcriptional inhibition of ER-α; however, there exists a controversy on whether BRCA1 induces or inhibits ER-α expression. The mechanisms associated with resistance of BRCA1 mutated cancers to hormone therapy, as well as the tissue restriction exhibited by BRCA1 mutated tumors are still largely unknown. BRCA1 mutated tumors possess increased DNA damages and decreased genomic integrity, as BRCA1 plays a cardinal role in high fidelity DNA damage repair pathways, like homologous recombination (HR). The existence of cross regulatory signaling networks between ER-α and BRCA1 speculates a role of ER on BRCA1 dependent DDR pathways. Thus, the loss or haploinsufficiency of BRCA1 and the consequential deregulation of ER-α signaling may result in persistence of unrepaired DNA damages, eventually leading to tumorigenesis. Therefore, understanding of this cross-talk between ER-α and BRCA1, with regard to DDR, will provide critical insights to steer drug development and therapy for breast/ovarian cancers. This review discusses the mechanisms by which estrogen and ER signaling influence BRCA1 mediated DNA damage response and repair pathways in the mammalian system.

In-silico analysis of gymnemagenin from Gymnema sylvestre (Retz.) R.Br. with targets related to diabetes.

Diabetes is a metabolic disorder characterized by higher than normal glucose in the blood. Most oral hypoglycemic drugs available in market produce adverse side effects which have resulted in continued search for new therapeutic agents with little or no side effects. Herbal drugs are considered relatively safer alternatives and Gymnema sylvestre is one of the most well established natural remedy for diabetes and is traded worldwide under several brands. In the present study an attempt has been made to use in silico techniques to understand and predict the drug likeliness of gymnemagenin, one of the key constituents of G. sylvestre against 15 proteins having key role in carbohydrate metabolism. Gymnemagenin was found to dock well with crystallographic structures of 7 of the 15 selected targets and was found even better than the two known clinically used antidiabetic compounds, repaglinide and sitagliptin taken in the study for comparison. Gymnemagenin therefore can be considered further for development into a potent anti-diabetic drug.