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Breast cancer remains a leading cause of mortality among women worldwide, with drug resistance driven by transcription factors and mutations posing significant challenges. To address this, we present ResisenseNet, a predictive model for drug sensitivity and resistance. ResisenseNet integrates transcription factor expression, genomic markers, drugs, and molecular descriptors, employing a hybrid architecture of 1D-CNN + LSTM and DNN to effectively learn long-range and temporal patterns from amino acid sequences and transcription factor data. The model demonstrated exceptional predictive accuracy, achieving a validation accuracy of 0.9794 and a loss value of 0.042. Comprehensive validation included comparisons with state-of-the-art models and ablation studies, confirming the robustness of the developed architecture. ResisenseNet has been applied to repurpose existing anticancer drugs across 14 different cancers, with a focus on breast cancer. Among the malignancies studied, drugs targeting Low-grade Glioma (LGG) and Lung Adenocarcinoma (LUAD) showed increased sensitivity to breast cancer as per ResisenseNet's assessment. Further evaluation of the predicted sensitive drugs revealed that 14 had no prior history of anticancer activity against breast cancer. These drugs target key signaling pathways involved in breast cancer, presenting novel therapeutic opportunities. ResisenseNet addresses drug resistance by filtering ineffective compounds and enhancing chemotherapy for breast cancer. In vitro studies on sensitive drugs provide valuable insights into breast cancer prognosis, contributing to improved treatment strategies. [ABSTRACT FROM AUTHOR]

Globally, breast cancer stands as the most prevalent form of cancer among women. The tumor microenvironment of breast cancer often exhibits hypoxia. Hypoxia-inducible factor 1-alpha, a transcription factor, is found to be overexpressed and activated in breast cancer, playing a pivotal role in the anoxic microenvironment by mediating a series of reactions. Hypoxiainducible factor 1-alpha is involved in regulating downstream pathways and target genes, which are crucial in hypoxic conditions, including glycolysis, angiogenesis, and metastasis. These processes significantly contribute to breast cancer progression by managing cancer-related activities linked to tumor invasion, metastasis, immune evasion, and drug resistance, resulting in poor prognosis for patients. Consequently, there is a significant interest in Hypoxia-inducible factor 1-alpha as a potential target for cancer therapy. Presently, research on drugs targeting Hypoxia-inducible factor 1-alpha is predominantly in the preclinical phase, highlighting the need for an in-depth understanding of HIF-1α and its regulatory pathway. It is anticipated that the future will see the introduction of effective HIF-1α inhibitors into clinical trials, offering new hope for breast cancer patients. Therefore, this review focuses on the structure and function of HIF-1α, its role in advancing breast cancer, and strategies to combat HIF-1α-dependent drug resistance, underlining its therapeutic potential. [ABSTRACT FROM AUTHOR]

Summary: The cellular stress and immunity cycle is a cornerstone of organismal homeostasis. Stress activates intracellular and intercellular communications within a tissue or organ to initiate adaptive responses aiming to resolve the origin of this stress. If such local measures are unable to ameliorate this stress, then intercellular communications expand toward immune activation with the aim of recruiting immune cells to effectively resolve the situation while executing tissue repair to ameliorate any damage and facilitate homeostasis. This cellular stress‐immunity cycle is severely dysregulated in diseased contexts like cancer. On one hand, cancer cells dysregulate the normal cellular stress responses to reorient them toward upholding growth at all costs, even at the expense of organismal integrity and homeostasis. On the other hand, the tumors severely dysregulate or inhibit various components of organismal immunity, for example, by facilitating immunosuppressive tumor landscape, lowering antigenicity, and increasing T‐cell dysfunction. In this review we aim to comprehensively discuss the basis behind tumoral dysregulation of cellular stress‐immunity cycle. We also offer insights into current understanding of the regulators and deregulators of this cycle and how they can be targeted for conceptualizing successful cancer immunotherapy regimen. [ABSTRACT FROM AUTHOR]

In this study, 21 new honokiol derivatives were synthesised, and their anti-cancer properties were investigated. Among these, compound 1g exhibited the most potent cytotoxic activity against human nasopharyngeal carcinoma CNE-2Z cells, human gastric cancer SGC7901 cells, human breast cancer MCF-7 cells, and mouse leydig testicular cancer I-10 lines with IC50 values of 6.04, 7.17, 6.83, and 5.30 μM, respectively. Compared to the parental compound, 1g displayed up to 5.18-fold enhancement of the cytotoxic effect on CNE-2Z cells. We further demonstrated that 1g inhibited cell growth, suppressed migration and invasion, and induced apoptosis of CNE-2Z cells by down-regulating HIF-1α, MMP-2, MMP-9, Bcl-2, Akt and up-regulating Bax protein levels. Transfection of CNE-2Z cells with HIF-1α siRNA reduced cell migration and invasion. In addition, in vivo experiments confirmed that 1g inhibited tumour growth in CNE-2Z cell-xenografted nude mice with low toxicity. Thus, our data suggested that 1g was a potent and safe lead compound for nasopharyngeal carcinoma therapy. [ABSTRACT FROM AUTHOR]

Purpose: Epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR–TKIs) are the first-line therapy for patients with lung adenocarcinoma (LUAD) harboring activating EGFR mutations. However, the emergence of drug resistance to EGFR–TKIs remains a critical obstacle for successful treatment and is associated with poor patient outcomes. The overarching objective of this study is to apply bioinformatics tools to gain insights into the mechanisms underlying resistance to EGFR–TKIs and develop a robust predictive model. Methods: The genes associated with gefitinib resistance in the LUAD cell Gene Expression Omnibus (GEO) database were identified using gene chip expression data. Functional enrichment analysis, gene set enrichment analysis (GSEA), and immune infiltration analysis were performed to comprehensively explore the mechanism of gefitinib resistance. Furthermore, a GRRG_score was constructed by integrating genes related to LUAD prognosis from The Cancer Genome Atlas (TCGA) database with the screened Gefitinib Resistant Related differentially expressed genes (GRRDEGs) using the Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analyses. Furthermore, we conducted an in-depth analysis of the tumor microenvironment (TME) features and their association with immune infiltration between different GRRG_score groups. A prognostic model for LUAD was developed based on the GRRG_score and validated. The HPA database was used to validate protein expression. The CTR-DB database was utilized to validate the results of drug therapy prediction based on the relevant genes. Results: A total of 110 differentially expression genes were identified. Pathway enrichment analysis of DEGs showed that the differentially expressed genes were mainly enriched in Mucin type O-glycan biosynthesis, Cytokine–cytokine receptor interaction, Sphingolipid metabolism. Gene set enrichment analysis showed that biological processes strongly correlated with gefitinib resistance were cell proliferation and immune-related pathways, EPITHELIAL_MESENCHYMAL_TRANSITION, APICAL_SURFACE, and APICAL_JUNCTION were highly expressed in the drug-resistant group; KRAS_SIGNALING_DN, HYPOXIA, and HEDGEHOG_SIGNALING were highly expressed in the drug-resistant group. The GRRG_score was constructed based on the expression levels of 13 genes, including HSPA2, ATP8B3, SPOCK1, EIF6, NUP62CL, BCAR3, PCSK9, NT5E, FLNC, KRT8, FSCN1, ANGPTL4, and ID1. We further screened and validated two key genes, namely, NUP62CL and KRT8, which exhibited predictive value for both prognosis and drug resistance. Conclusions: Our study identified several novel GRRDEGs and provided insight into the underlying mechanisms of gefitinib resistance in LUAD. Our results have implications for developing more effective treatment strategies and prognostic models for LUAD patients. [ABSTRACT FROM AUTHOR]

The increasing number of cancer-associated deaths despite the substantial improvement in diagnosis and treatment has sparked discussions on the need for novel biomarkers and therapeutic strategies for cancer. Exosomes have become crucial players in tumor development and progression, largely due to the diverse nature of their cargo content released to recipient cells. Importantly, exosome-mediated crosstalk between tumor and stromal cells is essential in reprogramming the tumor microenvironment to facilitate tumor progression. As a result, exosomes have gradually become a marker for the early diagnosis of many diseases and an important tool in drug delivery systems. However, the precise mechanisms by which exosomes participate in tumor progression remain elusive, multifaceted, and a double-edged sword, thus requiring further clarification. The available evidence suggests that exosomes can facilitate communication between innate immune cells and tumor cells to either support or inhibit tumor progression. Herein, this review focused on exosome-mediated intercellular communication between tumor cells and macrophages, neutrophils, mast cells, monocytes, dendritic cells, and natural killer cells. Specifically, how such intercellular communication affects tumor progression has been described. It has also been discussed that, depending on their cargo, exosomes can suppress or promote tumor cell progression. In addition, the potential application of exosomes and strategies to target exosomes in cancer treatment has been comprehensively discussed. [ABSTRACT FROM AUTHOR]

The microenvironment role is very important in cancer development. The epithelial–mesenchymal transition of the cancer cells depends upon specific signaling and microenvironmental conditions, such as hypoxic conditions. The crosstalk between hypoxia and Wnt signaling through some molecular mechanism in TNBC is related. Cross-communication between hypoxia and Wnt signaling in cancer cells is known, but the detailed mechanism in TNBC is unknown. This review includes the role of the hypoxia microenvironment in TNBC and the novel crosstalk of the Wnt signaling and hypoxia. When targeted, the new pathway and crosstalk link may be a solution for metastatic TNBC and chemoresistance. The microenvironment influences cancer's metastasis, which changes from person to person. Therefore, organ-on-a-chip is a very novel model to test the drugs clinically before going for human trials, focusing on personalized medications can be done. The effect of the hypoxia microenvironment on breast cancer stem cells is still unknown. Apart from all the published papers, this paper mainly focuses only on the hypoxic microenvironment and its association with the growth of TNBC. The medicines or small proteins, drugs, mimics, and inhibitors targeting wnt and hypoxia genes are consolidated in this review paper. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker. Methods: A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA. Results: In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours. Conclusion: Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs. [ABSTRACT FROM AUTHOR]

Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies. [ABSTRACT FROM AUTHOR]

Adequate oxygen levels are essential for the functioning and maintenance of biological processes in virtually every cell, albeit based on specific need. Thus, any change in oxygen pressure leads to modulated activation of the hypoxia pathway, which affects numerous physiological and pathological processes, including hematopoiesis, inflammation, and tumor development. The Hypoxia Inducible Factors (HIFs) are essential transcription factors and the driving force of the hypoxia pathway; whereas, their inhibitors, HIF prolyl hydroxylase domain (PHDs) proteins are the true oxygen sensors that critically regulate this response. Recently, we and others have described the central role of the PHD/HIF axis in various compartments of the adrenal gland and its potential influence in associated tumors, including pheochromocytomas and paragangliomas. Here, we provide an overview of the most recent findings on the hypoxia signaling pathway in vivo, including its role in the endocrine system, especially in adrenal tumors. [ABSTRACT FROM AUTHOR]

Breast cancer is a kind of malignant tumor disease that poses a serious threat to human health. Its biological characteristics of rapid proliferation and delayed angiogenesis, lead to intratumoral hypoxia as a common finding in breast cancer. HIF as a transcription factor, mediate a series of reactions in the hypoxic microenvironment, including metabolic reprogramming, tumor angiogenesis, tumor cell proliferation and metastasis and other important physiological and pathological processes, as well as gene instability under hypoxia. In addition, in the immune microenvironment of hypoxia, both innate and acquired immunity of tumor cells undergo subtle changes to support tumor and inhibit immune activity. Thus, the elucidation of tumor microenvironment hypoxia provides a promising target for the resistance and limited efficacy of current breast cancer therapies. We also summarize the hypoxic mechanisms of breast cancer treatment related drug resistance, as well as the current status and prospects of latest related drugs targeted HIF inhibitors. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women worldwide with increasing incidence. Significant therapeutics advances in the field of breast cancer have resulted in a growing number of treatment options, whereas de novo or acquired resistance is still a persistent clinical challenge. Drug resistance involves a variety of mechanisms, and hypoxia is one of the many causes. Hypoxia-inducible Factor-1 Alpha (HIF-1α) is a key transcription factor which can regulate the response of cells to hypoxia. HIF-1α can trigger anaerobic glycolysis of tumor cells, induce angiogenesis, promote the proliferation, invasion, and migration of tumor cells, and lead to multidrug resistance. This review mainly discusses the role of HIF-1α in the drug-resistant breast cancer and highlighted the potential of HIF-1α -targeted therapy. [ABSTRACT FROM AUTHOR]

Almost all solid tumors display hypoxic areas in the tumor microenvironment associated with therapeutic failure. It is now well established that the abnormal growth of malignant solid tumors exacerbates their susceptibility to hypoxia. Therefore, targeting hypoxia remains an attractive strategy to sensitize tumors to various therapies. Tumor cell adaptions to hypoxia are primarily mediated by hypoxia-inducible factor-1 alpha (HIF-1α). Sensing hypoxia by HIF-1α impairs the apoptotic potential of tumor cells, thus increasing their proliferative capacity and contributing to the development of a chaotic vasculature in the tumor microenvironment. Therefore, in addition to the negative impact of hypoxia on tumor response to chemo- and radio-therapies, hypoxia has also been described as a major hijacker of the tumor response by impairing the tumor cell susceptibility to immune cell killing. This review is not intended to provide a comprehensive overview of the work published by several groups on the multiple mechanisms by which hypoxia impairs the anti-tumor immunity and establishes the immunosuppressive tumor microenvironment. There are several excellent reviews highlighting the value of targeting hypoxia to improve the benefit of immunotherapy. Here, we first provide a brief overview of the mechanisms involved in the establishment of hypoxic stress in the tumor microenvironment. We then discuss our recently published data on how targeting hypoxia, by deleting a critical domain in HIF-1α, contributes to the improvement of the anti-tumor immune response. Our aim is to support the current dogma about the relevance of targeting hypoxia in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. MicorRNAs (miRNA) have been considered a promising therapeutic strategy in various cancers. Here, we identified the crucial function of miR-526b-3p in regulating PTX resistance and CSC properties. Our data demonstrated that miR-526b-3p mimic repressed the cell viability of breast cancer cells. The counts of Edu-positive cells were reduced by miR-526b-3p in breast cancer cells. Meanwhile, the apoptosis of breast cancer cells was induced by miR-526b-3p. Tumorigenicity analysis in the nude mice confirmed that miR-526b-3p attenuated the breast cancer cell growth in vivo. Significantly, hypoxia could enhance IC50 value of PTX in breast cancer cells. IC50 value of PTX was induced in breast cancer mammospheres. The hypoxia-inducible factor 2α (HIF-2α) expression was enhanced, but miR-526b-3p expression was repressed under hypoxia in breast cancer cells. Also, breast cancer mammospheres presented high HIF-2α expression and low miR-526b-3p expression. The inhibition of miR-526b-3p enhanced the IC50 value of PTX in breast cancer cells. MiR-526b-3p inhibitor enhanced the colony formation counts of PTX-treated breast cancer cells. The treatment of miR-526b-3p mimic suppressed the sphere formation counts of breast cancer cells and inhibited ALDH1 and Nanog expression. MiR-526b-3p was able to target HIF-2α in the cells. The overexpression enhanced but miR-526b-3p reduced the IC50 value of PTX in breast cancer cells, in which the overexpression of HIF-2α could rescue the miR-526b-3p-inhibited IC50 value of PTX. Overexpression of HIF-2α reversed miR-526b-3p-regulated apoptosis, colony formation ability, and ALDH1 and Nanog expression in the cells. Interestingly, the overexpression of HIF-2α induced but miR-526b-3p repressed the expression of HIF-2α, Hey2, and Notch in PTX-treated breast cancer cells, while HIF-2α could reverse the effect of miR-526b-3p. In conclusion, miR-526b-3p attenuated breast cancer stem cell properties and chemoresistance by targeting HIF-2α/Notch signaling. MiR-526b-3p may be utilized in the relieving chemoresistance in breast cancer. [ABSTRACT FROM AUTHOR]

Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM‐resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM‐resistant cells. It also enhanced the TAM‐induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan–Meier plotter database showed that HIF‐1α expression was inversely correlated with TAM therapeutic response in NCI‐60 cancer cells and breast cancer patients. HIF‐1α expression was increased in TAM‐resistant cells due to an increase in mRNA levels and reduced ubiquitin‐mediated degradation. Baicalein reduced HIF‐1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase‐mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia‐response element, and transcriptional activity of HIF‐1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF‐1α‐targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF‐1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM‐induced mitochondrial apoptotic pathway. The HIF‐1α stabilizer dimethyloxallyl glycine prevented the baicalein‐induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM‐induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF‐1α–mediated aerobic glycolysis and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]