Exploring HMMR as a therapeutic frontier in breast cancer treatment, its interaction with various cell cycle genes, and targeting its overexpression through specific inhibitors.

Among women, breast carcinoma is one of the most complex cancers, with one of the highest death rates worldwide. There have been significant improvements in treatment methods, but its early detection still remains an issue to be resolved. This study explores the multifaceted function of hyaluronan-mediated motility receptor (HMMR) in breast cancer progression. HMMR's association with key cell cycle regulators (AURKA, TPX2, and CDK1) underscores its pivotal role in cancer initiation and advancement. HMMR's involvement in microtubule assembly and cellular interactions, both extracellularly and intracellularly, provides critical insights into its contribution to cancer cell processes. Elevated HMMR expression triggered by inflammatory signals correlates with unfavorable prognosis in breast cancer and various other malignancies. Therefore, recognizing HMMR as a promising therapeutic target, the study validates the overexpression of HMMR in breast cancer and various pan cancers and its correlation with certain proteins such as AURKA, TPX2, and CDK1 through online databases. Furthermore, the pathways associated with HMMR were explored using pathway enrichment analysis, such as Gene Ontology, offering a foundation for the development of effective strategies in breast cancer treatment. The study further highlights compounds capable of inhibiting certain pathways, which, in turn, would inhibit the upregulation of HMMR in breast cancer. The results were further validated via MD simulations in addition to molecular docking to explore protein-protein/ligand interaction. Consequently, these findings imply that HMMR could play a pivotal role as a crucial oncogenic regulator, highlighting its potential as a promising target for the therapeutic intervention of breast carcinoma.

Metronomic chemotherapy and drug repurposing: A paradigm shift in oncology.

Cancer represents a significant global health and economic burden due to its high mortality rates. While effective in some instances, traditional chemotherapy often falls short of entirely eradicating various types of cancer. It can cause severe side effects due to harm to healthy cells. Two therapeutic approaches have risen to the forefront to address these limitations: metronomic chemotherapy (MCT) and drug repurposing. Metronomic chemotherapy is an innovative approach that breaks from traditional models. It involves the administration of chemotherapeutic regimens at lower doses, without long drug-free intervals that have previously been a hallmark of such treatments. This method offers a significant reduction in side effects and improved disease management. Simultaneously, drug repurposing has gained considerable attraction in cancer treatment. This approach involves utilizing existing drugs, initially developed for other therapeutic purposes, as potential cancer treatments. The application of known drugs in a new context accelerates the timeline from laboratory to patient due to pre-existing safety and dosage data. The intersection of these two strategies gives rise to a novel therapeutic approach named 'Metronomics.' This approach encapsulates the benefits of both MCT and drug repurposing, leading to reduced toxicity, potential for oral administration, improved patient quality of life, accelerated clinical implementation, and enhanced affordability. Numerous clinical studies have endorsed the efficacy of metronomic chemotherapy with tolerable side effects, underlining the potential of Metronomics in better cancer management, particularly in low- and middle-income countries. This review underscores the benefits and applications of metronomic chemotherapy and drug repurposing, specifically in the context of breast cancer, showcasing the promising results of pre-clinical and clinical studies. However, we acknowledge the necessity of additional clinical investigations to definitively establish the role of metronomic chemotherapy in conjunction with other treatments in comprehensive cancer management.

Decoding the molecular mechanism of stypoldione against breast cancer through network pharmacology and experimental validation.

Breast cancer is the primary factor contributing to female mortality worldwide. The incidence has overtaken lung cancer. It is the most difficult illness due to its heterogeneity and is made up of several subtypes, including Luminal A and B, basal-like, Her-2 overexpressed and TNBC. Amongst different breast carcinoma subtypes, TNBC is the most deadly breast cancer subtype. The hostile nature of TNBC is mainly attributed to its lack of three hormonal receptors and hence lack of targeted therapy. Furthermore, the current diagnostic options like radiotherapy, surgery and chemotherapy render unsuccessful due to recurrence, treatment side effects and drug resistance. The majority of anticancer drugs come from natural sources or is developed from them, making nature a significant source of many medicines. Marine-based constituents such as nucleotides, proteins, peptides, and amides are receiving a lot of interest in the field of cancer treatment due to their bioactive properties. The role of stypoldione in this study as a prospective treatment for breast carcinoma was examined, and we sought to comprehend the molecular means/pathways this chemical employs in breast carcinoma. The most promising possibility for an anti-cancer treatment is stypoldione, a marine chemical produced from the brown alga Stypopodium zonale. We investigated stypoldione's mode of action in breast cancer using the network pharmacology method, and we confirmed our research by using a number of computational tools, including UALCAN, cBioportal, TIMER, docking, and simulation. The findings revealed 92 common targets between the chemical and breast cancer target network. Additionally, we found that stypoldione targets a number of unregulated genes in breast cancer, including: ESR1, HSP90AA1, CXCL8, PTGS2, APP, MDM2, JAK2, KDR, LCK, GRM5, MAPK14, KIT, and several signaling pathways such as FOXO signaling pathway, VEGF pathway, calcium signaling pathway, MAPK/ERK pathway and Neuroactive ligand-receptor interaction. The examined medication demonstrated a strong affinity for the major targets, according to a docking analysis. The best hit compound produced a stable protein-ligand pair, as predicted by molecular dynamics simulations. Our results are supported by the fact that when in-vitro assays were done on melanoma using stypoldione compound it was found that its mechanisms of action involved the PI3K/mTOR/Akt and NF-kB pathways. This study was set out to inspect the possible value of stypoldione as a breast cancer cure and to get a deeper understanding of the molecular mechanisms by which this drug acts on breast cancer.

Targeting breast cancer stem cells through retinoids: A new hope for treatment.

Breast cancer is a complex and diverse disease accounting for nearly 30% of all cancers diagnosed in females. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. With over half a million deaths annually, it is imperative to explore new therapeutic approaches to combat the disease. Within a breast tumor, a small sub-population of heterogeneous cells, with a unique ability of self-renew and differentiation and responsible for tumor formation, initiation, and recurrence are referred to as breast cancer stem cells (BCSCs). These BCSCs have been identified as one of the main contributors to chemoresistance in breast cancer, making them an attractive target for developing novel therapeutic strategies. These cells exhibit surface biomarkers such as CD44+, CD24-/LOW, ALDH, CD133, and CD49f phenotypes. Higher expression of CD44+ and ALDH activity has been associated with the formation of tumors in various cancers. Moreover, the abnormal regulation of signaling pathways, including Hedgehog, Notch, ß-catenin, JAK/STAT, and P13K/AKT/mTOR, leads to the formation of cancer stem cells, resulting in the development of tumors. The growing drug resistance in BC is a significant challenge, highlighting the need for new therapeutic strategies to combat this dreadful disease. Retinoids, a large group of synthetic derivatives of vitamin A, have been studied as chemopreventive agents in clinical trials and have been shown to regulate various crucial biological functions including vision, development, inflammation, and metabolism. On a cellular level, the retinoid activity has been well characterized and translated and is known to induce differentiation and apoptosis, which play important roles in the outcome of the transformation of tissues into malignant. Retinoids have been investigated extensively for their use in the treatment and prevention of cancer due to their high receptor-binding affinity to directly modulate gene expression programs. Therefore, in this study, we aim to summarize the current understanding of BCSCs, their biomarkers, and the associated signaling pathways. Retinoids, such as Adapalene, a third-generation retinoid, have shown promising anti-cancer potential and may serve as therapeutic agents to target BCSCs.

Elucidation of interleukin-19 as a therapeutic target for breast cancer by computational analysis and experimental validation.

Interleukin 19 (IL-19) is a cytokine produced by monocytes and belongs to the family of IL-10. The IL-19 protein stimulates fibronectin (FN) expression and assembly, metastasis, and cell division in breast cancer (BC) cells. IL-19, which is connected to breast pathogenesis and has an autocrine action in BC cells, is a key predictor of prognosis for many tumour forms, including breast cancer. Augmented IL-19 expression has been related to poorer clinical outcomes for patients with BC and directly enhances proliferation and migration while also serving as a microenvironment for tumour formation. The main aim of our study was to examine the expression profile, functional role, and prognostic significance of interleukin-19 in BC pathogenesis and also to find out the molecular mechanism of IL-19 in BC. In this work, we used the various computational approach and tools, to evaluate the expression profile and prognostic implication of IL-19 in BC and discover the role of IL-19 in BC pathogenesis. IL-19 was shown to be highly upregulated in BC as compared to other interleukins. Also, its levels were highly overexpressed in liminal BC patients, mostly in 3rd stage groups under the age group of 21-40 years. IL-19 levels were increased in BC and elevated expression of IL-19 was examined to have worse overall survival (OS). The KEGG analysis and gene ontology of IL-19 depict that IL-19 is significantly augmented in cytokine activity and receptor-ligand activity and also in the JAK-STAT signaling pathway. Moreover, IL-19 showed a high correlation with IL20RA, as later is involved with the JAK-STAT signaling pathway. The in-vivo and in-vitro studies have also reflected that upregulation of IL-19 enhances tumor development and affects clinical outcomes in BC patients through several pathways including the JAK TAT signalling pathway. Overall, our study indicates that IL-19 increases tumour growth and that inhibiting it in addition to standard treatments will greatly improve BC patient's therapeutic responses.

Mechanistic elucidation of Juglanthraquinone C targeting breast Cancer: A network Pharmacology-based investigation.

Breast cancer is the leading cause of death among women worldwide. Despite the recent treatment options like surgery, chemotherapy etc. the lethality of breast cancer is alarming. Natural compounds are considered a better treatment option against breast carcinoma because of their lower side effects and specificity in targeting important proteins involved in the aberrant activation of pathways in breast cancer. A recently discovered compound called Juglanthraquinone C, which is found in the bark of the Juglans mandshurica Maxim (Juglandaceae) tree has shown promising cytotoxicity in hepatocellular carcinoma. However, not much data is available on the molecular mechanisms followed by this compound. Therefore, we aimed to investigate the molecular mechanism followed by Juglanthraquinone C against breast cancer. We used the network pharmacology technique to analyse the mechanism of action of Juglanthraquinone C in breast cancer and validated our study by applying various computational tools such as UALCAN, cBioportal, TIMER, docking and simulation. The results showed the compound and breast cancer target network shared 31 common targets. Moreover, we observed that Juglanthraquinone C targets multiple deregulated genes in breast cancer such as TP53, TGIF1, IGF1R, SMAD3, JUN, CDC42, HBEGF, FOS and signaling pathways such as PI3K-Akt pathway, TGF-ß signaling pathway, MAPK pathway and HIPPO signaling pathway. A docking examination revealed that the investigated drug had a high affinity for the primary target TGIF1 protein. A stable protein-ligand combination was generated by the best hit molecule, according to molecular dynamics modeling. The main aim of this study was to examine Juglanthraquinone C's significance as a prospective breast cancer treatment and to better understand the molecular mechanism this substance uses in breast cancer since there is a need to discover new therapeutics to decrease the load on current therapeutics which also are currently ineffective due to several side effects and development of drug resistance.

A network pharmacology-based investigation of brugine reveals its multi-target molecular mechanism against Breast Cancer.

Breast cancer represents the leading cause of mortality among women worldwide. Since the complexity of breast cancer as a disease resides in its heterogeneity as it consists of several subtypes such as hormone receptor-positive subtypes: Luminal A, Luminal B, Her2- overexpressed, basal-like and hormone receptor-negative subtype: TNBC. Among all the subtypes, triple negative breast cancer (TNBC) is the most lethal and complex subtype. Moreover, the available treatment options like surgery, radiation therapy, and chemotherapy are not sufficient because of the associated side effects and drug resistance development. Therefore, discovery of new effective natural compounds with anti-tumor activity is required. In this pursuit, marine organisms provide a plentiful supply of such chemicals compounds. A marine compound Brugine found in the bark and stem of mangrove species Bruguiera sexangula is a potential anti-cancer compound. It has shown its cytotoxic activity against sarcoma 180 and lewis lung cancer. The molecular processes, however, are currently unknown. So, in order to research the molecular pathways this compound utilizes, we sought to apply a network pharmacology approach. The network pharmacology strategy we used in this investigation to identify and evaluate possible molecular pathways involved in the treatment of breast cancer with brugine was supported by simulation and molecular docking experiments. The study was conducted using various databases such as the cancer genome atlas (TCGA) for the genetic profile study of breast cancer, Swiss ADME for studying the pharmacodynamic study of brugine, Gene cards for collection of information of genes, STRING was used to study the interaction among proteins, AutoDock vina was to study the binding efficacy of brugine with the best fit protein. The results showed that the compound and breast cancer target network shared 90 common targets. According to the functional enrichment analysis brugine exhibited its effects in breast cancer via modulating certain pathways such as cAMP signaling pathway, JAK/STAT pathway, HIF-1 signaling pathway PI3K-Akt pathway, calcium signaling pathway, and Necroptosis. Molecular docking investigations demonstrated that the investigated marine compound has a high affinity for the key target, protein kinase A (PKA). A stable protein-ligand combination was created by the best hit molecule, according to molecular dynamics modeling. The purpose of this research was to examine the importance of brugine as a potentially effective treatment for breast cancer and to obtain knowledge of the molecular mechanism used by this substance in breast cancer.

Targeting tumor microenvironment using tumor-infiltrating lymphocytes as therapeutics against tumorigenesis.

The immune system plays a vital role in suppressing tumor cell progression. The tumor microenvironment augmented with significant levels of tumor-infiltrating lymphocytes has been widely investigated and it is suggested that tumor-infiltrating lymphocytes have shown a significant role in the prognosis of cancer patients. Compared to ordinary non-infiltrating lymphocytes, tumor-infiltrating lymphocytes (TILs) are a significant population of lymphocytes that infiltrate tumor tissue and have a higher level of specific immunological reactivity against tumor cells. They serve as an effective immunological defense against various malignancies. TILs are a diverse group of immune cells that are divided into immune subsets based on the pathological and physiological impact they have on the immune system. TILs mainly consist of B-cells, T-cells, or natural killer cells with diverse phenotypic and functional properties. TILs are known to be superior to other immune cells in that they can recognize a wide range of heterogeneous tumor antigens by producing many clones of T cell receptors (TCRs), outperforming treatments like TCR-T cell and CAR-T therapy. With the introduction of genetic engineering technologies, tumor-infiltrating lymphocytes (TILs) have become a ground-breaking therapeutic option for malignancies, but because of the hindrances opposed by the immune microenvironment and the mutation of antigens, the development of TILs as therapeutic has been hindered. By giving some insight into the many variables, such as the various barriers inhibiting its usage as a potential therapeutic agent, we have examined various aspects of TILs in this work.

Targeting p53 misfolding conundrum by stabilizing agents and their analogs in breast cancer therapy: a comprehensive computational analysis.

Cancer continues to be a major global public health concern and one of the foremost causes of death. Delays in the diagnosis and cure may cause an increase in advanced stage disease and mortality. The most common cancer found in women currently is breast carcinoma. Breast carcinoma has surpassed lung carcinoma and currently represents the chief type of cancer diagnosed (2.3 million new cases, which amount to 11.7% of all cancer cases). In addition, by 2040, the incidence will increase by more than 46% as per the estimates of GLOBOCAN. Triple-negative breast cancer (TNBC) represents a highly aggressive and invasive subtype of breast cancer, characterized by rapid progression, short response time to the available treatment, and poor clinical results. Thus, it is very crucial to develop novel diagnostic tools and therapeutics with good efficacy. A majority of cancers display malfunction along the p53 pathway. Moreover, p53 not only loses its function but is also prone to misfolding and aggregation, leading to formation of amyloid aggregates as well. Research is being carried out to find ways to restore the normal action and expression of p53. Here, we have explored PhiKan-083 for its possible stabilizing effect on p53 in order to address the problem with its misfolding. Thus, examining the analogs of PhiKan-083 that have a role in p53 stability will help update our understanding of cancer progression and may expedite the progress of new anticancer treatments. We anticipate that the drug molecules and their analogs targeting p53 aggregation may be used in combination with other anticancer compounds to solve the problem with p53 aggregation. In this study, by employing ADMET analysis, the compounds were screened, and we further examined the chosen compounds with the help of molecular docking. By using databases like UALCAN, TIMER, GEPIA, and PredictProtein, we investigated TP53's expression pattern and prognostic relevance in various cancer settings.

Expression patterns and therapeutic implications of CDK4 across multiple carcinomas: a molecular docking and MD simulation study.

The CDKs are known to play a critical role in cell cycle regulation process. Among the different groups of CDKs, CDK4 overexpression/hyperactivation is found to be present in many cancers and a specific CDK4 inhibitor, palbociclib has been recently approved by the FDA against breast cancer. However, the treatment with palbociclib has shown many associated toxicities such as-anemia, thrombocytopenia, neutropenia, and febrile neutropenia and more. Despite the fact being FDA approved for only breast cancer and no other cancers and CDK4 being overexpressed in multiple cancers. Therefore, we in our study intend to screen two novel CDK4 inhibitors that show considerably less associated toxicities and greater therapeutic implications than palbociclib. We screened the compounds using Lipinski's rule, ADMET analysis and further analyzed the selected compounds using a virtual screening method called molecular docking and validated our results by MD simulation. We studied the expression patterns and prognostic significance of CDK4 across multiple carcinomas by using some database like UALCAN, cBioportal, and KM-Plotter.

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors.

Cell cycle dysregulation is a characteristic hallmark of malignancies, which results in uncontrolled cell proliferation and eventual tumor formation. Cyclin-dependent kinase 1 (CDK1) is a member of the family of cell cycle regulatory proteins involved in cell cycle maintenance. Given that overexpression of CDK1 has been associated with cancer, CDK1 inhibitors may restore equilibrium to the skewed cell cycle system and operate as an effective therapeutic drug. This study aimed to identify and classify inhibitors having a higher affinity for CDK1 and also evaluate the expression pattern and prognostic relevance of CDK1 in a wide range of cancers. We investigated therapeutic molecules structurally similar to dinaciclib for their ability to inhibit CDK1 selectively. To assess the therapeutic potential of screened Dinaciclib analogs, we used drug likeliness analysis, molecular docking, and simulation analysis. CDK1 was found to be highly upregulated across several malignancies and is associated with poor overall and relapse-free survival. Molecular docking and dynamics evaluation identified two novel dinaciclib analogs as potent CDK1 inhibitors with high binding affinity and stability compared to dinaciclib. The results indicate that increased CDK1 expression is associated with decreased OS and RFS. Additionally, dinaciclib analogs are prospective replacements for dinaciclib since they exhibit increased binding affinity, consistent with MDS findings, and have acceptable ADMET qualities. The discovery of new compounds may pave the road for their future application in cancer prevention through basic, preclinical, and clinical research.

Cyclin-dependent kinases in breast cancer: expression pattern and therapeutic implications.

Presently, breast cancer (BC) is one of the most common malignancies diagnosed and the leading cause of tumor-related deaths among women worldwide. Cell cycle dysregulation is one of the hallmarks of cancer, resulting in uncontrolled cell proliferation. Cyclin-dependent kinases (CDKs) are central to the cell cycle control system, and deregulation of these kinases leads to the development of malignancies, including breast cancer. CDKs and cyclins have been reported as crucial components involved in tumor cell proliferation and metastasis. Given the aggressive nature, tumor heterogeneity, and chemoresistance, there is an urgent need to explore novel targets and therapeutics to manage breast cancer effectively. Inhibitors targeting CDKs modulate the cell cycle, thus throwing light upon their therapeutic aspect where the progression of tumor cells could be inhibited. This article gives a comprehensive account of CDKs in breast cancer progression and metastasis and recent developments in the modulation of CDKs in treating malignancies. We have also explored the expression pattern and prognostic significance of CDKs in breast cancer patients. The article will also shed light on the Implications of CDK inhibition and TGF-ß signaling in breast cancer.

Cryptolepine Targets TOP2A and Inhibits Tumor Cell Proliferation in Breast Cancer Cells - An In vitro and In silico Study.

BACKGROUND: DNA Topoisomerase II Alpha (TOP2A), a protein-coding gene, is central to the replication process and has been found deregulated in several malignancies, including breast cancer. Several therapeutic regimens have been developed and approved for targeting TOP2A and have prolonged the survival of cancer patients. However, due to the inherent nature of the tumor cell to evolve, the earlier positive response turns into a refractory chemoresistance in breast cancer patients. OBJECTIVE: The study's main objective was to analyze the expression pattern and prognostic significance of TOP2A in breast cancer patients and screen new therapeutic molecules targeting TOP2A. METHODS: We utilized an integrated bioinformatic approach to analyze the expression pattern, genetic alteration, immune association, and prognostic significance of TOP2A in breast cancer (BC) and screened natural compounds targeting TOP2A, and performed an in silico and an in vitro analysis. RESULTS: Our study showed that TOP2A is highly overexpressed in breast cancer tissues and overexpression of TOP2A correlates with worse overall survival (OS) and relapse-free survival (RFS). Moreover, TOP2A showed a high association with tumor stroma, particularly with myeloid-derived suppressor cells. Also, in silico and in vitro analysis revealed cryptolepine as a promising natural compound targeting TOP2A. CONCLUSION: Cumulatively, this study signifies that TOP2A promotes breast cancer progression, and targeting TOP2A in combination with other therapeutic agents will significantly enhance the response of BC patients to therapy and reduce the development of chemoresistance.

An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most complex, aggressive and fatal subtype of breast cancer. Owing to the lack of targeted therapy and heterogenic nature of TNBC, chemotherapy remains the sole treatment option for TNBC, with taxanes and anthracyclines representing the general chemotherapeutic regimen in TNBC therapy. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. Breast cancer stem cells (BCSCs) are one of the major causes for the development of chemoresistance in TNBC patients. After surviving the chemotherapy damage, the presence of BCSCs results in relapse and recurrence of TNBC. Several pathways are known to regulate BCSCs' survival, such as the Wnt/ß-catenin, Hedgehog, JAK/STAT and HIPPO pathways. Therefore it is imperative to target these pathways in the context of eliminating chemoresistance. In this review we will discuss the novel strategies and various preclinical and clinical studies to give an insight into overcoming TNBC chemoresistance. We present a detailed account of recent studies carried out that open an exciting perspective in relation to the mechanisms of chemoresistance.

Prognostic significance and targeting tumor-associated macrophages in cancer: new insights and future perspectives.

Macrophages are phagocytic sentinel cells of the immune system that are central to both innate and adaptive immune responses and serve as the first line of defense against pathogenic insults to tissues. In the tumor microenvironment, tumor-derived factors induce monocyte polarization towards a pro-tumor phenotype. The pro-tumor macrophages regulate key steps in tumorigenicity including tumor growth, angiogenesis, immune suppression, and metastasis. Macrophage infiltration in solid tumors correlates with poor prognosis and resistance to chemotherapy in most cancers. Here in this review, we will shed light on tumor-associated macrophages (TAMs) in regulating tumorigenicity and TAMs as a prognostic biomarker. Also, we will review the recent advances in targeting TAMs to increase the prognosis of cancer patients.

Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer accounting for 15-20% of cases and is defined by the lack of hormonal receptors viz., estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth receptor 2 (HER2). Treatment of TNBC is more challenging than other subtypes of breast cancer due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/ Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Despite, TNBC being more chemo-responsive than other subtypes, unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance. Using a monotherapy for the treatment of cancer, especially high-grade tumors like TNBC, is mostly worthless due to the inherent genetic instability of tumor cells to develop intrinsic and acquired resistance. Thus, a cocktail of two or more drugs with different mechanisms of action is more effective and could successfully control the disease. Furthermore, combination therapy reveals more, or at least the same, effectiveness with lower doses of every single agent and decreases the likelihood of chemoresistance. Herein, we shed light on the novel combinatorial approaches targeting PARP, EGFR, PI3K pathway, AR, and wnt signaling, HDAC, MEK pathway for efficient treatment of high-grade tumors like TNBC and decreasing the onset of resistance.