• Breast cancer
• CRISPR/Cas9
• Cancer research
• Immune response
• Immunotherapy
• Knockout strategies
• Off-target effects
• Precision medicine
• Targeted genetic changes

• Humans
• CRISPR-Cas Systems
• Breast Neoplasms/genetics
• Breast Neoplasms/therapy
• Breast Neoplasms/immunology
• Immunotherapy/methods
• Female
• Animals
• Gene Knockout Techniques/methods
• Gene Editing/methods

• Chemotherapy resistance
• Diagnosis
• Long non-coding RNA (lncRNA)
• Prognosis
• Triple-negative breast cancer (TNBC)

• Humans
• Female
• Triple Negative Breast Neoplasms/diagnosis
• Triple Negative Breast Neoplasms/genetics
• RNA, Long Noncoding/genetics
• Biomarkers, Tumor/genetics
• Gene Expression Regulation, Neoplastic

• LBY21H160001 the Zhejiang Provincial Natural Science Foundation of China

• Tumor microenvironment
• breast cancer
• breast cancer metastasis suppressor 1
• metastasis suppressor genes

The immune system plays a fundamental role in neoplastic disease. In the era of immunotherapy, the adaptive immune response has been in the spotlight whereas the role of innate immunity in cancer development and progression is less known. The tumor microenvironment influences the terminal differentiation of innate immune cells, which can explicate their pro-tumor or anti-tumor effect. Different cells are able to recognize and eliminate no self and tumor cells: macrophages, natural killer cells, monocytes, dendritic cells, and neutrophils are, together with the elements of the complement system, the principal players of innate immunity in cancer development and evolution. Metastatic breast cancer is a heterogeneous disease from the stromal, immune, and biological point of view and requires deepened exploration to understand different patient outcomes. In this review, we summarize the evidence about the role of innate immunity in breast cancer metastatic sites and the potential targets for optimizing the innate response as a novel treatment opportunity.

The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER⁺), progesterone receptor-positive (PR⁺), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.

The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). This highly dynamic molecular network provides critical biochemical and biomechanical cues that mediate the cell–cell and cell–matrix interactions, influence cell growth, migration and differentiation and serve as a reservoir of cytokines and growth factors’ action. The breakdown of normal ECM and its replacement with tumor ECM modulate the tumor microenvironment (TME) composition and is an essential part of tumorigenesis and metastasis, acting as key driver for malignant progression. Abnormal ECM also deregulate behavior of stromal cells as well as facilitating tumor-associated angiogenesis and inflammation. Thus, the tumor matrix modulates each of the classically defined hallmarks of cancer promoting the growth, survival and invasion of the cancer. Moreover, various ECM-derived components modulate the immune response affecting T cells, tumor-associated macrophages (TAM), dendritic cells and cancer-associated fibroblasts (CAF). This review article considers the role that extracellular matrix play in breast cancer. Determining the detailed connections between the ECM and cellular processes has helped to identify novel disease markers and therapeutic targets.

• breast cancer
• extracellular matrix
• proteins
• tumor microenvironment
• tumorigenesis

• Animals
• Antineoplastic Agents, Phytogenic/adverse effects
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Drug Compounding
• Drug Synergism
• Female
• Humans
• Medical Oncology
• Nanomedicine
• Nanoparticles
• Paclitaxel/adverse effects
• Paclitaxel/chemistry
• Paclitaxel/therapeutic use

• Tonkinensine B
• anti-migration and anti-invasion
• apoptosis
• human triple-negative breast cancer
• mitochondria-mediated

• Cancer-associated fibroblasts
• Exosomes
• Extracellular matrix
• G-protein estrogen receptor
• Metabolism
• Warburg effect

• Chemoresistance
• Chemotherapeutic drugs
• Combination chemotherapy
• Death-related intracellular signaling
• Intracellular signaling
• Precision medicine
• Resistance-related intracellular signaling

• Adipocyte
• Fibroblast
• Macrophage
• Stromal cell
• Tumor evasion
• Tumor microenvironment

Breast cancer is a leading cancer type and one of the major health issues faced by women around the world. Some of its major risk factors include body mass index, hormone replacement therapy, family history and germline mutations. Of these risk factors, estrogen levels play a crucial role. Among the estrogen receptors, estrogen receptor alpha (ERα) is known to interact with tumor suppressor protein p53 directly thereby repressing its function. Previously, we have studied the impact of deleterious breast cancer-associated non-synonymous single nucleotide polymorphisms (nsnps) rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 gene on the p53 DNA-binding core domain. In the present study, we aimed to analyze the impact of these mutations on p53–ERα interaction. To this end, we, have modelled the full-length structure of human p53 and validated its quality using PROCHECK and subjected it to energy minimization using NOMAD-Ref web server. Three-dimensional structure of ERα activation function-2 (AF-2) domain was downloaded from the protein data bank. Interactions between the modelled native and mutant (R110P, P278A, P151T) p53 with ERα was studied using ZDOCK. Machine learning predictions on the interactions were performed using Weka software. Results from the protein–protein docking showed that the atoms, residues and solvent accessibility surface area (SASA) at the interface was increased in both p53 and ERα for R110P mutation compared to the native complexes indicating that the mutation R110P has more impact on the p53–ERα interaction compared to the other two mutants. Mutations P151T and P278A, on the other hand, showed a large deviation from the native p53-ERα complex in atoms and residues at the surface. Further, results from artificial neural network analysis showed that these structural features are important for predicting the impact of these three mutations on p53–ERα interaction. Overall, these three mutations showed a large deviation in total SASA in both p53 and ERα. In conclusion, results from our study will be crucial in making the decisions for hormone-based therapies against breast cancer.

• ERα
• TP53
• breast cancer
• genetic factors
• machine learning
• single nucleotide polymorphism

• Computational Biology/methods
• Estrogen Receptor alpha/chemistry
• Estrogen Receptor alpha/metabolism
• Humans
• Machine Learning
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Mutation
• Neural Networks, Computer
• Polymorphism, Single Nucleotide
• Protein Binding
• Protein Conformation
• Protein Interaction Domains and Motifs
• Structure-Activity Relationship
• Tumor Suppressor Protein p53/chemistry
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• Acetylcholinesterase
• Neural inflammation
• Neuropsychotic diseases
• Pesticides
• Serine protease

• Abnormalities, Drug-Induced/epidemiology
• Abnormalities, Drug-Induced/etiology
• Africa
• Agricultural Workers' Diseases/chemically induced
• Farmers
• Female
• Humans
• India
• Male
• Neoplasms/chemically induced
• Neoplasms/epidemiology
• Occupational Exposure/adverse effects
• Pesticides/analysis
• Pesticides/toxicity
• Psychotic Disorders/epidemiology
• Psychotic Disorders/etiology
• Suicide/trends
• United States

• Breast cancer
• Endocrine disruption
• Estrogenic
• Inflammations
• Lifestyle revision

• Animals
• Breast Neoplasms/drug therapy
• Breast Neoplasms/etiology
• Breast Neoplasms/pathology
• Complementary Therapies/methods
• Estrogens/therapeutic use
• Female
• Humans
• Life Style
• Selective Estrogen Receptor Modulators/therapeutic use

• Biomarkers
• Breast cancer
• Checkpoint inhibitor
• Clinical trials
• Immunotherapy
• Review

• Green tea polyphenol (GTP); Breast cancer; MCF-7 cells; Mitochondrial-mediated apoptosis; Cell death; Cell cycle arrest

The relationship of the immune system and tumour cells is complex; although recognised that the immune system can protect the host against tumour development, the immune system also facilitates tumour progression through immune suppression. Pro-inflammatory mediators associated with chronic inflammation are responsible for the expansion and activation of myeloid derived suppressor cells (MDSCs); a heterogeneous group of cells that originates from myeloid progenitor cells but does not complete the final stages of differentiation. A causal relationship between chronic inflammation and tumour progression relies on the accumulation and maintenance of MDSCs as its linchpin; responsible for immunosuppression through the down-regulation of anti-tumour responses. MDSCs cause immunosuppression through a number of mechanisms; inhibiting the proliferation of CD4⁺ and CD8⁺ T cells, blocking natural killer cell activation and limiting dendritic cell maturation and function. As well as using various mechanisms to inhibit adaptive and immune responses, MDSCs also have non-immunological functions that aid tumour spread; including directly promoting tumour proliferation and metastasis by having an important role in tumour angiogenesis, secretion of matrix metalloproteinases and induction of epithelial-mesenchymal transition. Breast cancer is the most common cancer among women in the United Kingdom with 44540 new cases of invasive carcinoma in 2013 and results in the second highest cancer mortality rate in women, with 11600 deaths in 2012. Considering this, the need for novel therapeutic interventions is higher than ever. This review summarises the rationale for the targeting of MDSCs in breast cancer as a realistic avenue to increase survival from breast cancer.

• Breast cancer
• Immune cells
• Treatment
• Suppression
• Survival

• Antineoplastic Combined Chemotherapy Protocols
• Cisplatin/therapeutic use
• Drug Resistance, Neoplasm
• Female
• Humans
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/immunology
• Ovarian Neoplasms/pathology
• Paclitaxel/immunology
• Paclitaxel/therapeutic use
• Taxoids/immunology
• Taxoids/therapeutic use

• VEGF
• VEGFR
• antiangiogenic drugs
• breast cancer
• monoclonal antibodies
• tyrosine kinases inhibitors

Alloimmune inflammation damages the microvasculature of solid organ transplants during acute rejection. Although immunosuppressive drugs diminish the inflammatory response, they do not directly promote vascular repair. Repetitive microvascular injury with insufficient regeneration results in prolonged tissue hypoxia and fibrotic remodeling. While clinical studies show that a loss of the microvascular circulation precedes and may act as an initiating factor for the development of chronic rejection, preclinical studies demonstrate that improved microvascular perfusion during acute rejection delays and attenuates tissue fibrosis. Therefore, preservation of a functional microvasculature may represent an effective therapeutic strategy for preventing chronic rejection. Here, we review recent advances in our understanding of the role of the microvasculature in the long-term survival of transplanted solid organs. We also highlight microvessel-centered therapeutic strategies for prolonging the survival of solid organ transplants.