STAT Family of Transcription Factors in Breast Cancer: Pathogenesis and Therapeutic Opportunities and Challenges.

Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients.

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Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer

Nepenthes are carnivorous pitcher plants that have several ethnobotanical uses, such as curing stomachache and fever. Here, we prepared different extracts from the stem, leaf, and pitcher of Nepenthes miranda to further investigate their pharmacological potential. The leaf extract of N. miranda obtained by 100% acetone (N. miranda-leaf-acetone) was used in this study to analyze the cytotoxic activities, antioxidation capacity, antibacterial activity, and allantoinase (ALLase) inhibitory effect of this plant. The cytotoxic effects of N. miranda-leaf-acetone on the survival, apoptosis, and migration of the cancer cell lines PC-9 pulmonary adenocarcinoma, B16F10 melanoma, and 4T1 mammary carcinoma cells were demonstrated. Based on collective data, the cytotoxic activities of N. miranda-leaf-acetone followed the order: B16F10 > 4T1 > PC-9 cells. In addition, the cytotoxic activities of N. miranda-leaf-acetone were synergistically enhanced when co-acting with the clinical anticancer drug 5-fluorouracil. N. miranda-leaf-acetone could also inhibit the activity of ALLase, a key enzyme in the catabolism pathway for purine degradation. Through gas chromatography–mass spectrometry, the 16 most abundant ingredients in N. miranda-leaf-acetone were identified. The top six compounds in N. miranda-leaf-acetone, namely, plumbagin, lupenone, palmitic acid, stigmast-5-en-3-ol, neophytadiene, and citraconic anhydride, were docked to ALLase, and their docking scores were compared. The docking results suggested plumbagin and stigmast-5-en-3-ol as potential inhibitors of ALLase. Overall, these results may indicate the pharmacological potential of N. miranda for further medical applications.

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Cytotoxic Activities and the Allantoinase Inhibitory Effect of the Leaf Extract of the Carnivorous Pitcher Plant Nepenthes miranda

Enterobacter cloacae is mainly responsible for sepsis, urethritis, and respiratory tract infections. These bacteria may affect the transcription of the host and particularly their immune system by producing changes in their epigenetics. In the present study, four proteins of Enterobacter cloacae were used to predict the epitopes for the construction of an mRNA vaccine against Enterobacter cloacae infections. In order to generate cellular and humoral responses, various immunoinformatic-based approaches were used for developing the vaccine. The molecular docking analysis was performed for predicting the interaction among the chosen epitopes and corresponding MHC alleles. The vaccine was developed by combining epitopes (thirty-three total), which include the adjuvant Toll-like receptor-4 (TLR4). The constructed vaccine was analyzed and predicted to cover 99.2% of the global population. Additionally, in silico immunological modeling of the vaccination was also carried out. When it enters the cytoplasm of the human (host), the codon is optimized to generate the translated mRNA efficiently. Moreover, the peptide structures were analyzed and docked with TLR-3 and TLR-4. A dynamic simulation predicted the stability of the binding complex. The assumed construct was considered to be a potential candidate for a vaccine against Enterobacter cloacae infections. Hence, the proposed construct is suitable for in vitro analyses to validate its effectiveness.

https://www.mdpi.com/2076-2607/10/8/1621/pdf?version=1660131301

Regulation of Host Immune Response against Enterobacter cloacae Proteins via Computational mRNA Vaccine Design through Transcriptional Modification

Prostate cancer is the most common cancer and is the second leading cause of cancer-related deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard treatment for advanced-stage prostate cancer; however, this treatment eventually fails, leading to an incurable disease subtype known as metastatic castration-resistant prostate cancer (mCRPC). There are several molecular mechanisms that facilitate the development of mCRPC engaging androgen receptor (AR) growth axis, including AR amplification, gain of function AR mutations, and AR splice variants that are constitutively active and are a foremost factor for mCRPC development. AR-independent mechanisms with exceptionally low or absent AR expression found in cancer cells suppress ADT effectiveness and contribute to aggressive variants, including neuroendocrine differentiation. Several other AR regulatory factors such as epigenetic modification(s), and DNA damage response have been reported during post-ADT exposure and play a crucial role in mCRPC development. Therefore, targeting prostate cancer cells before their progression to mCRPC would improve patient outcomes. This special issue in "Cancer Drug Resistance" focuses on understanding the mechanism(s) and development of mCRPC resistance. This special issue also highlights the therapeutic strategies to combat against resistant subtype. This issue comprehensively reviews the mCRPC and delivers the update in the forum of mCRPC resistance development. 

/pdf/new-insights-for-drug-resistance-in-metastatic-castration-wdre6meg.pdf

New insights for drug resistance in metastatic castration-resistant prostate cancer

Breast cancer is a heterogeneous disease consisting of atypical cell populations that share stem cell‐like characteristics associated with therapeutic resistance, disease relapse, and poor clinical outcome. MicroRNAs (miRNA), and small noncoding RNA, are pivotal in the regulation of self‐renewal, stemness, and cellular differentiation. Withaferin A (WA), a steroidal lactone, is a major bioactive constituent of Withania somnifera (Solanaceae) known for its anticancer properties. In this study, the effect of WA on modulation of miRNA expression in breast cancer‐derived mammosphere was assessed utilizing small RNA sequencing. Treatment with WA inhibited MCF‐7 and T47D cells derived mammosphere formation with a significant decrease in CD44, EpCAM, Nanog, OCT4, and SOX2 as markers of self‐renewal and stemness. Small RNA sequencing demonstrated a total of 395 differentially expressed miRNAs (DEMs) including 194 upregulated and 201 downregulated miRNAs in WA‐treated MCF‐7 mammospheres. Bioinformatics analysis utilizing the KEGG pathway, Gene Ontology enrichment, protein−protein, and miRNA‐mRNA interaction network identified altered expression in a few hub genes viz. AKT1, PTEN, MYC, CCND1, VEGFA, NOTCH1, and IGFR1 associated with DEMs in WA‐treated mammospheres. Further quantitative RT‐PCR analysis validated the expression of DEMs including miR‐549a‐5p, miR‐1247‐5p, miR‐124‐5p, miR‐137‐5p, miR‐34a‐5p, miR‐146a‐5p, miR‐99a‐5p, miR‐181a‐5p, let‐7c‐5p, and let‐7a‐5p. In particular, let‐7c‐5p is designated as a tumor suppressor in breast cancer. An increase in miR‐let‐7c‐5p expression was noted after WA treatment, with a simultaneous decrease in CCND1 and c‐MYC at mRNA and protein levels. Taken together, our study demonstrated WA‐mediated miRNA expression, in particular, upregulation of miR‐let‐7c‐5p, leads to the inhibition of breast cancer cells derived mammospheres.

Withaferin A mediated changes of miRNA expression in breast cancer‐derived mammospheres

Androgen deprivation therapy (ADT) is the standard of care treatment for advance stage prostate cancer. Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer (CRPC). Present research establishes that prostate cancer stem-like cells (CSCs) play a central role in the development of treatment resistance followed by disease progression. Prostate CSCs are capable of self-renewal, differentiation, and regenerating tumor heterogeneity. The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants, epigenetic and genetic modifications leading to alteration in the tumor microenvironment, changes in ATP-binding cassette (ABC) transporters, and adaptations in molecular signaling pathways. ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), Prominin 1 (PROM1/CD133), Indian blood group (CD44), SRY-Box Transcription Factor 2 (Sox2), POU Class 5 Homeobox 1(POU5F1/Oct4), Nanog and ABC transporters. These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution, metastatic colonization, and resistance to antiandrogens. In this review, we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC, their isolation, identification and characterization, as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.

/pdf/role-of-prostate-cancer-stem-like-cells-in-the-development-3fgflt0p.pdf

Role of prostate cancer stem-like cells in the development of antiandrogen resistance

A candidate triple-negative breast cancer vaccine design by targeting clinically relevant cell surface markers: an integrated immuno and bio-informatics approach

Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (∆G) in the M46I–saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease.

/pdf/drug-resistance-mechanism-of-m46i-mutation-induced-k2m6311i.pdf

Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation

Simple Summary Luminal A subtype breast cancer is the most prevalent form of breast malignancy with frequent diagnosis in women. Breast cancer stem cells (BCSCs) are a rare population of cells present therein that cause cancer aggressiveness, relapse, drug-resistance, poor therapeutic outcome and a decrease in overall survival of these patients. The published literature indicates that dietary phytochemicals have the potential to target stemness and self-renewal properties in luminal A-derived BCSCs. The aim of this review is to highlight the anticancer potential of dietary phytochemicals against luminal A-derived BCSCs and their underlying mechanism(s). These findings necessitate in-depth preclinical and clinical studies on phytochemicals to explore their role in breast cancer prevention and treatment. Abstract Breast cancer is heterogeneous disease with variable prognosis and therapeutic response. Approximately, 70% of diagnosed breast cancer represents the luminal A subtype. This subpopulation has a fair prognosis with a lower rate of relapse than the other clinical subtypes. Acquisition of stemness in luminal A subtype modifies the phenotype plasticity to accomplish increased aggressiveness and therapeutic resistance. Therefore, targeting luminal A-derived breast cancer stem cells (BCSCs) could be a promising strategy for its prevention and treatment. Extensive studies reveal that dietary phytochemicals have the potential to target BCSCs by modulating the molecular and signal transduction pathways. Dietary phytochemicals alone or in combination with standard therapeutic modalities exert higher efficacy in targeting BCSCs through changes in stemness, self-renewal properties and hypoxia-related factors. These combinations offer achieving higher radio- and chemo- sensitization through alteration in the key signaling pathways such as AMPK, STAT3, NF-ĸB, Hedgehog, PI3K/Akt/mTOR, Notch, GSK3β, and Wnt related to cancer stemness and drug resistance. In this review, we highlight the concept of targeting luminal A-derived BCSCs with dietary phytochemicals by summarizing the pathways and underlying mechanism(s) involved during therapeutic resistance.

/pdf/targeting-breast-cancer-derived-stem-cells-by-dietary-10jmr6ti.pdf

Sanjay Gupta

Papers

Withaferin A mediated changes of miRNA expression in breast cancer‐derived mammospheres

Role of prostate cancer stem-like cells in the development of antiandrogen resistance

A candidate triple-negative breast cancer vaccine design by targeting clinically relevant cell surface markers: an integrated immuno and bio-informatics approach

Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation

Targeting Breast Cancer-Derived Stem Cells by Dietary Phytochemicals: A Strategy for Cancer Prevention and Treatment