Common single nucleotide polymorphisms associated with idiopathic pulmonary fibrosis: a systematic review.

BACKGROUND: Several genetic variants are associated with the risk of idiopathic pulmonary fibrosis (IPF). These have not been systematically reviewed. METHODS: We searched the PubMed, Embase and GWAS Catalog databases for studies indexed between inception and 15 January 2024 describing genetic variants associated with IPF susceptibility. We included studies describing common associated single nucleotide polymorphisms (SNPs). We excluded studies describing rare variants, non-SNP variants and those without an allelic model analysis. We recorded study type, participant characteristics, genotyping methods, IPF diagnostic criteria, the SNPs and the respective genes, odds ratios, and other details. We also searched databases for functions of the identified genes. RESULTS: The primary search retrieved 2697 publications; we included 42 studies. There were nine genome-wide association/linkage studies, while 27 were candidate gene studies. The studies included 22-11 160 IPF subjects. 88 SNPs in 58 genes or loci were found associated with IPF susceptibility. MUC5B rs35705950 was the most studied SNP. Most (n=51) SNPs were in the intronic or intergenic regions; only 11 were coding sequence variants. The SNPs had odds ratios ranging from 0.27 to 7.82 for an association with IPF. Only 22 SNPs had moderate-large effects (OR >1.5 or <0.67). Only 49.1% of the associated genes have a known functional role in IPF; the role of G protein-related signalling and transcriptional regulation (zinc-finger proteins) remain unexplored. CONCLUSION: Several common SNPs in over 50 genes have been found associated with IPF susceptibility. These variants may inform gene panels for future studies (PROSPERO CRD42023408912).

Utilizing Next-Generation Sequencing: Advancements in the Diagnosis of Fungal Infections.

Next-generation sequencing (NGS) has emerged as a promising tool for diagnosing fungal infections. It enables the identification of a wide range of fungal species and provides more accurate and rapid results than traditional diagnostic methods. NGS-based approaches involve the sequencing of DNA or RNA from clinical samples, which can be used to detect and identify fungal pathogens in complex clinical samples. The development of targeted gene panels and whole-genome sequencing has allowed for identifying genetic markers associated with antifungal drug resistance, enabling clinicians to tailor patient treatment options. NGS can also provide insights into the pathogenesis of fungal infections and aid in discovering novel drug targets. Although NGS has some limitations, such as cost and data analysis, it can potentially revolutionize the future diagnosis and treatment of fungal infections.

Targeting Interleukin-13 Receptor α2 and EphA2 in Aggressive Breast Cancer Subtypes with Special References to Chimeric Antigen Receptor T-Cell Therapy.

Breast cancer (BCA) remains the leading cause of cancer-related mortality among women worldwide. This review delves into the therapeutic challenges of BCA, emphasizing the roles of interleukin-13 receptor α2 (IL-13Rα2) and erythropoietin-producing hepatocellular receptor A2 (EphA2) in tumor progression and resistance. Highlighting their overexpression in BCA, particularly in aggressive subtypes, such as Her-2-enriched and triple-negative breast cancer (TNBC), we discuss the potential of these receptors as targets for chimeric antigen receptor T-cell (CAR-T) therapies. We examine the structural and functional roles of IL-13Rα2 and EphA2, their pathological significance in BCA, and the promising therapeutic avenues their targeting presents. With an in-depth analysis of current immunotherapeutic strategies, including the limitations of existing treatments and the potential of dual antigen-targeting CAR T-cell therapies, this review aims to summarize potential future novel, more effective therapeutic interventions for BCA. Through a thorough examination of preclinical and clinical studies, it underlines the urgent need for targeted therapies in combating the high mortality rates associated with Her-2-enriched and TNBC subtypes and discusses the potential role of IL-13Rα2 and EphA2 as promising candidates for the development of CAR T-cell therapies.

Primary Rosai-Dorfman disease of the central nervous system: A clinical, histological, and molecular appraisal.

Rosai-Dorfman disease (RDD) is characterized by clonal proliferation of S-100 positive histiocytes and variable emperipolesis. It commonly affects cervical lymph nodes. Central nervous system (CNS) involvement is extremely rare. We attempted to evaluate the Cyclin D1 expression and frequency of KRAS and BRAF mutations in the RDD involving the CNS. All patients with histopathologically diagnosed RDD involving CNS were recruited from 2011 to 2022. All cases were subjected to immunohistochemistry for CD68, CD163, S100, CD1a, GFAP, CD207, EMA, ALK, BRAFV600E, IgG4, IgG, and CyclinD1. The real-time polymerase chain reaction (RT-PCR) for hotspot mutation analysis of KRAS (exons 2, 3, and 4) and BRAF (V600E) was conducted on formalin-fixed paraffin-embedded tissue using a commercial kit (EntroGen). A total of seven cases were included. The median age was 31 years, with six men and one woman. It showed spinal cord (n = 4) and intracranial (n = 3) involvement. Histologically, all cases showed histiocyte-rich inflammation with evidence of emperipolesis. These histiocytes were positive for S100, CD68, CD163, and Cyclin D1, whereas negative for CD1a, CD207, and EMA. BRAF V600E was expressed in a single case. None of the control cases (demyelination and infarction) with histiocytic infiltrate showed Cyclin D1 expression. Four RDD cases showed increased IgG4-positive plasma cells (>10/HPF) and IgG4/IgG ratio (>40%). BRAF V600E mutation was detected in one case (14.28%), while none showed KRAS mutation. RDD involving CNS is extremely rare and diagnostically challenging. Nuclear Cyclin D1 expression along with S-100 positivity in the tumor cells is a strong diagnostic clue. BRAF and KRAS mutations are rare in CNS RDD.

Cancer associated fibroblasts modulate the cytotoxicity of anti-cancer drugs in breast cancer: An in vitro study.

BACKGROUND: Tumour microenvironment (TME) contributes to resistance to anti-cancer drugs through multiple mechanisms including secretion of pro-survival factors by cancer associated fibroblasts (CAFs). In this study, we determined the chemotherapy resistance producing potential of CAFs in molecular subtypes of breast cancer. METHODS: The CAFs were isolated from fresh lumpectomy/mastectomy specimens of different molecular subtypes of breast cancer. The CAFs were cultured and secretome was collected from each breast cancer subtype. Breast cancer cell lines MCF-7, SK-BR3, MDA-MB-231, and MDA-MB-468 were treated with different doses of tamoxifen, trastuzumab, cisplatin, and doxorubicin alone respectively and in combination with secretome of CAFs from respective subtypes. MTT assay was done to check cell death after drug treatment. Liquid chromatography-mass spectrometry (LCMS) analysis of CAF secretome was also done. RESULTS: MTT assay showed that anti-cancer drugs alone had growth inhibitory effect on the cancer cells however, presence of CAF secretome reduced the anti-cancer effect of the drugs. Resistant to drugs in the presence of secretome, was determined by increased cell viability i.e., MCF-7, 51.02% to 63.02%; SK-BR-3, 34.22% to 44.88%; MDA-MB-231, 52.59% to 78.63%; and MDA-MB-468, 48.92% to 55.08%. LCMS analysis of the secretome showed the differential abundance of CAFs secreted proteins across breast cancer subtypes. CONCLUSIONS: The treatment of breast cancer cell lines with anti-cancer drugs in combination with secretome isolated from molecular subtype specific CAFs, reduced the cytotoxic effect of the drugs. In addition, LCMS data also highlighted different composition of secreted proteins from different breast cancer associated fibroblasts. Thus, TME has heterogenous population of CAFs across the breast cancer subtypes and in vitro experiments highlight their contribution to chemotherapy resistance which needs further validation.

Osteopontin in cancer.

Osteopontin (OPN) is a heavily post-translationally modified protein with a molecular weight of 44-70 kDa, depending on the degree of glycosylation. OPN is involved in various biological processes, including bone remodeling, immune response, cell adhesion, migration, and survival. It is essential for controlling osteoclast and osteoblast activity for maintaining bone mass and bone strength. Additionally, OPN has been linked to cardiovascular, inflammatory illnesses, as well as the onset and progression of cancer. OPN is a multifunctional protein that can interact with a variety of cell surface receptors, such as integrins, CD44, the urokinase-type plasminogen activator receptor (uPAR), as well as extracellular matrix (ECM) components (e.g. collagen and hydroxyapatite). These interactions contribute to its wide range of biological functions in general and has significant implications for bone biology, immunology and cancer, specifically. In this chapter, we summarize the structure of OPN with a focus on its molecular mechanisms of action in various cancers.

Stevens-johnson Syndrome and Toxic Epidermal Necrolysis: An Overview of Diagnosis, Therapy Options and Prognosis of Patients.

Both Stevens-johnson syndrome (SJS) and Toxic-epidermal necrolysis (TEN) are generally medication-induced pathological conditions that mostly affect the epidermis and mucus membranes. Nearly 1 to 2 patients per 1,000,000 population are affected annually with SJS and TEN, and sometimes these maladies can cause serious life-threatening events. The reported death rates for SJS range from 1 to 5%, and 25 to 35% for TEN. The mortality risk may even be higher among elderly patients, especially in those who are affected by a significant amount of epidermal detachment. More than 50% of TEN patients who survive the illness may experience long-term lower quality of life and lesser life expectancy. The clinical and histopathological conditions of SJS and TEN are characterized by mucocutaneous discomfort, haemorrhagic erosions, erythema, and occasionally severe epidermal separation that can turn into ulcerative patches and dermal necrosis. The relative difference between SJS and TEN is the degree of ulcerative skin detachment, making them two extremes of a spectrum of severe cutaneous adverse drug-induced reactions (cADRs). In the majority of cases, serious drug-related hypercreativities are considered the main cause of SJS & TEN; however, herpes simplex virus and Mycoplasma pneumoniae infections may also produce similar type clinical conditions. The aetiology of a lesser number of cases and their underlying causative factors remain unknown. Among the drugs with a 'greater likelihood' of causing TEN & SJS are carbamazepine (CBZ), trimethoprim-sulfamethoxazole, phenytoin, aminopenicillins, allopurinol, cephalosporins, sulphonamides, antibiotics, quinolones, phenobarbital, and NSAIDs of the oxicam variety. There is also a strong genetic link between the occurrence of SJS and IEN in the Han Chinese population. Such genetic association is based on the human leukocyte antigen (HLA-B*1502) and the co-administration of carbamazepine. The diagnosis of SJS is made mostly on the gross observations of clinical symptoms, and confirmed by the histopathological examination of dermal biopsies of the patients. The differential diagnoses consist of the exclusion of Pemphigus vulgaris, bullous pemphigoid, linear IgA dermatosis, paraneoplastic pemphigus, disseminated fixed bullous drug eruption, acute generalized exanthematous pustulosis (AGEP), and staphylococcal scalded skin syndrome (SSSS). The management of SJS & TEN is rather difficult and complicated, and there is sometimes a high risk of mortality in seriously inflicted patients. Urgent medical attention is needed for early diagnosis, estimation of the SCORTEN prognosis, identification and discontinuation of the causative agent as well as highdose injectable Ig therapeutic interventions along with specialized supportive care. Historical aspects, aetiology, mechanisms, and incidences of SJS and TEN are discussed. An update on the genetic occurrence of these medication-related hypersensitive ailments as well as different therapy options and management of patients is also provided.

Heterogeneity of the Tumor Microenvironment Across Molecular Subtypes of Breast Cancer.

Breast cancer is a heterogenous disease at the molecular level thus, it can be hypothesized that different molecular subtypes differ in their tumor microenvironment (TME) also. Understanding the TME heterogeneity may provide new prognostic biomarkers and new targets for cancer therapy. For deciphering heterogeneity in the TME, immunohistochemistry for immune markers (CD3, CD4, CD8, CD68, CD163, and programmed death-ligand 1), Cancer-associated fibroblast markers [anti-fibroblast activating protein α (FAP-α), platelet-derived growth factor receptor α (PDGFR-α), S100A4, Neuron-glial antigen 2, and Caveolin-1], and angiogenesis (CD31) was performed on tissue microarrays of different molecular subtypes of breast cancer. High CD3 + T cells were noted in the Luminal B subtype ( P =0.002) of which the majority were CD8 + cytotoxic T cells. Programmed death-ligand 1 expression in immune cells was highest in the human epidermal growth factor receptor 2 (Her-2)-positive and Luminal B subtypes compared with the triple-negative breast cancer (TNBC) subtype ( P =0.003). Her-2 subtype is rich in M2 tumor-associated macrophages ( P =0.000) compared with TNBC and Luminal B subtypes. M2 immune microenvironment correlated with high tumor grade and high Ki-67. Her-2 and TNBC subtypes are rich in extracellular matrix remodeling (FAP-α, P =0.003), angiogenesis-promoting (PDGFR-α; P =0.000) and invasion markers (Neuron-glial antigen 2, P =0.000; S100A4, P =0.07) compared with Luminal subtypes. Mean Microvessel density showed an increasing trend: Luminal A>Luminal B>Her-2 positive>TNBC; however, this difference was not statistically significant. The cancer-associated fibroblasts (FAP-α, PDGFR-α, and Neuron-glial antigen 2) showed a positive correlation with lymph node metastasis in specific subtypes. Immune cells, tumor-associated macrophage, and cancer-associated fibroblast-related s tromal markers showed higher expression in Luminal B, Her-2 positive, and TNBC respectively. This differential expression of different components of TME indicates heterogeneity of the TME across molecular subtypes of breast cancer.

Global Increase in Breast Cancer Incidence: Risk Factors and Preventive Measures.

Breast cancer is a global cause for concern owing to its high incidence around the world. The alarming increase in breast cancer cases emphasizes the management of disease at multiple levels. The management should start from the beginning that includes stringent cancer screening or cancer registry to effective diagnostic and treatment strategies. Breast cancer is highly heterogeneous at morphology as well as molecular levels and needs different therapeutic regimens based on the molecular subtype. Breast cancer patients with respective subtype have different clinical outcome prognoses. Breast cancer heterogeneity emphasizes the advanced molecular testing that will help on-time diagnosis and improved survival. Emerging fields such as liquid biopsy and artificial intelligence would help to under the complexity of breast cancer disease and decide the therapeutic regimen that helps in breast cancer management. In this review, we have discussed various risk factors and advanced technology available for breast cancer diagnosis to combat the worst breast cancer status and areas that need to be focused for the better management of breast cancer.

Coding roles of long non-coding RNAs in breast cancer: Emerging molecular diagnostic biomarkers and potential therapeutic targets with special reference to chemotherapy resistance.

Dysregulation of epigenetic mechanisms have been depicted in several pathological consequence such as cancer. Different modes of epigenetic regulation (DNA methylation (hypomethylation or hypermethylation of promotor), histone modifications, abnormal expression of microRNAs (miRNAs), long non-coding RNAs, and small nucleolar RNAs), are discovered. Particularly, lncRNAs are known to exert pivot roles in different types of cancer including breast cancer. LncRNAs with oncogenic and tumour suppressive potential are reported. Differentially expressed lncRNAs contribute a remarkable role in the development of primary and acquired resistance for radiotherapy, endocrine therapy, immunotherapy, and targeted therapy. A wide range of molecular subtype specific lncRNAs have been assessed in breast cancer research. A number of studies have also shown that lncRNAs may be clinically used as non-invasive diagnostic biomarkers for early detection of breast cancer. Such molecular biomarkers have also been found in cancer stem cells of breast tumours. The objectives of the present review are to summarize the important roles of oncogenic and tumour suppressive lncRNAs for the early diagnosis of breast cancer, metastatic potential, and chemotherapy resistance across the molecular subtypes.

Intrinsic and extrinsic pathways of apoptosis: Role in cancer development and prognosis.

Apoptosis, also named programmed cell death, is a fundament process required for morphogenetic homeostasis during early development and in pathophysiological conditions. It is come into existence in 1972 by work of Kerr, Wyllie and Currie and later on investigated during the research on development of the C. elegans. Trigger by several stimuli, apoptosis is necessary during the embryonic development and aging as homeostatic mechanism to control the cell population and also play a key role as defense mechanism against the immune responses and elimination of damaged cells. Cancer, a genetic disease, is a growing burden on the health and economy of both developing and developed countries. Every year there is tremendously increasing in the number of new cancer cases and mortality rate. Although, there is a significant improvement have been made in biotechnological and bioinformatic fields however, the therapeutic advantages and cancer etiology is still under explored. Several studies determined the deregulation of different apoptotic components during the cancer development and progression. Apoptosis relies on activation of distinct signaling pathways that are often deregulated in cancer. Thus, exploring the single or more than one apoptotic component underlying their expression in carcinogenesis could help to track the disease progression. Current book chapter will provide the several evidences supporting the use of different apoptotic components as prognosis and prediction markers in various human cancer types.

Oncogenic and Tumor Suppressive Components of the Cell Cycle in Breast Cancer Progression and Prognosis.

Cancer, a disease of inappropriate cell proliferation, is strongly interconnected with the cell cycle. All cancers consist of an abnormal accumulation of neoplastic cells, which are propagated toward uncontrolled cell division and proliferation in response to mitogenic signals. Mitogenic stimuli include genetic and epigenetic changes in cell cycle regulatory genes and other genes which regulate the cell cycle. This suggests that multiple, distinct pathways of genetic alterations lead to cancer development. Products of both oncogenes (including cyclin-dependent kinase (CDKs) and cyclins) and tumor suppressor genes (including cyclin-dependent kinase inhibitors) regulate cell cycle machinery and promote or suppress cell cycle progression, respectively. The identification of cyclins and CDKs help to explain and understand the molecular mechanisms of cell cycle machinery. During breast cancer tumorigenesis, cyclins A, B, C, D1, and E; cyclin-dependent kinase (CDKs); and CDK-inhibitor proteins p16, p21, p27, and p53 are known to play significant roles in cell cycle control and are tightly regulated in normal breast epithelial cells. Following mitogenic stimuli, these components are deregulated, which promotes neoplastic transformation of breast epithelial cells. Multiple studies implicate the roles of both types of components-oncogenic CDKs and cyclins, along with tumor-suppressing cyclin-dependent inhibitors-in breast cancer initiation and progression. Numerous clinical studies have confirmed that there is a prognostic significance for screening for these described components, regarding patient outcomes and their responses to therapy. The aim of this review article is to summarize the roles of oncogenic and tumor-suppressive components of the cell cycle in breast cancer progression and prognosis.

ALK-Negative Anaplastic Large Cell Lymphoma (ALCL): Prognostic Implications of Molecular Subtyping and JAK-STAT Pathway.

The anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a clinically distinct but heterogeneous entity and lacks the specific immunophenotypic or genetic features compared with the ALK-positive ALCL. Recent molecular studies have provided genetic landscapes of ALK-negative ALCL that have prognostic significance. In this study, we subtyped ALK-negative ALCL based on DUSP22 rearrangements and TP63 expression and also looked for mutations in JAK-STAT pathway. The subtyping of the ALK-negative ALCL in relation to DUSP22 rearrangement and TP63 expression was done using fluorescence in situ hybridization and immunohistochemistry, respectively. The hotspot JAK-STAT mutations were analyzed using Sanger sequencing and amplification refractory mutation system polymerase chain reaction (PCR) and Signal transducer and activator of transcription 3 (STAT3) expression by immunohistochemistry. Forty-eight cases of ALCL were included with median age of 30 years and sex ratio of 1.8:1. The p63 expression was detected in 26.7% of ALK-negative ALCL cases. DUSP22 rearrangement was noted in 12.5% cases of p63-negative ALK-negative ALCLs. DUSP22 rearranged cases had better overall survival in contrast to p63 expressing and triple negative ALCLs. Triple negative ALCLs showed inferior overall survival rate. STAT3 expression was evident in 61.1% and 60% of ALK-positive and ALK-negative ALCLs, respectively. None of the cases subjected to Sanger sequencing as well as amplification refractory mutation system PCR for hotspot mutation analysis of JAK1 (exon 24) and STAT3 (exon 21) revealed any mutation. ALK-negative ALCL is a genetically heterogeneous disease with widely disparate clinical outcomes. Subtyping of ALK-negative ALCL based on DUSP22 rearrangement and p63 expression provides prognostic information.

The relative expression levels of CD148 and CD180 on clonal B cells and CD148/CD180 median fluorescence intensity ratios are useful in the characterization of mature B cell lymphoid neoplasms infiltrating blood and bone marrow - Results from a single centre pilot study.

INTRODUCTION: The categorization of mature B cell neoplasms (MBN) infiltrating blood and bone marrow are met with difficulties. The inclusion of CD148 and CD180 in the routine flow cytometry/FCM panels has been suggested to refine the diagnosis. We studied the discriminatory ability of CD148 and CD180 median fluorescence intensity(MFI), CD148/CD180 ratio and their expression relative to T cells (CD148ab/T , CD180ab/T ), neutrophils (CD148ab/gr , CD180ab/gr ) and normal B cells (CD148ab/n , CD180ab/n ) in the differentiation of mature B cell neoplasms (MBN) especially non-chronic lymphocytic leukaemia (CLL). METHODOLOGY: The flow cytometric (FCM) expression of CD148 and CD180 was studied prospectively in 102 patients (non-CLL; n = 72); diagnosed by a comprehensive panel of immunophenotypic and cytogenetic studies. The MFI and ratios were statistically compared across MBNs by Mann-Whitney U test. Cut-off values, sensitivity and specificity were calculated for significant parameters by receiver operator characteristic curve. RESULTS: CD180MFI > 4.35 showed 100% sensitivity and 90.9% specificity for a diagnosis of marginal zone lymphoma (MZL) while, CD148/180 > 5.15 was 100% specific and 81.8% sensitive for lymphoplasmacytic lymphoma. CD148ab/T (>4.3; 100% specificity, 83.4% sensitivity) and CD148ab/gr (>1.1; 100% sensitivity, 90% sensitivity) were useful for differentiating blastoid-mantle cell lymphoma/MCL from diffuse large B cell lymphoma; while CD148MFI (≥20.25), CD148ab/T (>3.35) and CD148ab/gr (>0.95) showed >90% specificity and sensitivity for distinguishing MCL from CLL. Pairwise analysis also showed a good discriminant function of various parameters for distinguishing SMZL from other MBNs like FL, MCL as well as CLL. CONCLUSIONS: The current study shows an excellent utility of CD148MFI, CD180MFI, their ratio and relative expression levels in the subcategorization of immunophenotypically related MBNs.

Natural product-based nanoformulations for cancer therapy: Opportunities and challenges.

Application of natural product-based nanoformulations for the treatment of different human diseases, such as cancer, is an emerging field. The conventional cancer therapeutic modalities, including surgery, chemotherapy, immunotherapy, radiotherapy has limited achievements. A larger number of drawbacks are associated with these therapies, including damage to proliferating healthy tissues, structural deformities, systemic toxicity, long-term side effects, resistance to the drug by tumor cells, and psychological problems. The advent of nanotechnology in cancer therapeutics is recent; however, it has progressed and transformed the field of cancer treatment at a rapid rate. Nanotherapeutics have promisingly overcome the limitations of conventional drug delivery system, i.e., low aqueous solubility, low bioavailability, multidrug resistance, and non-specificity. Specifically, natural product-based nanoformulations are being intentionally studied in different model systems. Where it is found that these nanoformulations has more proximity and reduced side effects. The nanoparticles can specifically target tumor cells, enhancing the specificity and efficacy of cancer therapeutic modalities which in turn improves patient response and survival. The integration of phytotherapy and nanotechnology in the clinical setting may improve pharmacological response and better clinical outcome of patients.

Cell-free miRNAs as non-invasive biomarkers in breast cancer: Significance in early diagnosis and metastasis prediction.

Breast cancer is one of the genetic diseases causing a high mortality among women around the world. Despite the availability of advanced diagnostic tools and treatment strategies, the incidence of breast cancer is increasing every year. This is due to the lack of accurate and reliable biomarkers whose deficiency creates difficulty in early breast cancer recognition, subtypes determination, and metastasis prophecy. Although biomarkers such as ER, PR, Her2, Ki-67, and other genetic platforms e.g. MammaPrint®, Oncotype DX®, Prosigna® or EndoPredict® are available for determination of breast cancer diagnosis and prognosis. However, pertaining to heterogeneous nature, lack of sensitivity, and specificity of these markers, it is still incessant to overcome breast cancer burden. Therefore, a novel biomarker is urgently needed for therapeutic diagnosis and improving prognosis. Lately, it has become more evident that cell-free miRNAs might be useful as good non-invasive biomarkers that are associated with different events in carcinogenesis. For example, some known biomarkers such as miR-21, miR-23a, miR-34a are associated with molecular subtyping and different biomolecular aspects i.e. apoptosis, angiogenesis, metastasis, and miR-1, miR-10b, miR-16 are associated with drug response. Cell-free miRNAs present in human body fluids have proven to be potential biomarkers with significant prognostic and predictive values. Numerous studies have found a distinct expression profile of circulating miRNAs in breast tumour versus non-tumour and in early and advanced-stage, thus implicating its clinical relevance. This review article will highlight the importance of different cell-free miRNAs as a biomarker for early breast cancer detection, subtype classification, and metastasis forecast.

Tumour angiogenesis and c-Met pathway activation - implications in breast cancer.

Breast cancer is a heterogeneous disease with wide range of clinical behaviour. Tumour angiogenesis and metastasis have been considered as prognostic markers of the breast carcinoma, and c-Met, a transmembrane receptor tyrosine kinase has been implicated in both these processes of tumour progression. This study was conducted to elucidate c-Met and downstream signalling pathways in breast cancer and correlate with angiogenesis as assessed by microvessel density (MVD) and other prognostic parameters including lymph node metastases. Microvessel density (MVD) was assessed by endothelial cell (CD34) marker in breast cancers. c-Met was evaluated by immunohistochemistry for protein expression and by copy number assay for amplification at gene level. PCR array for gene expression related to c-Met, RAS-MAPK, PI3K-AKT and angiogenesis pathway was performed by real-time PCR. c-Met protein, copy number and mRNA expression did not differ significantly with the lymph node status or MVD. However, Her-2 overexpressing group showed c-Met protein overexpression and amplification. c-Met protein overexpression was also noted in the Luminal B subtype though no amplification was noted. Thus, the c-Met immunohistochemistry score and the c-MET copy numbers did not correlate with each other. c-Met downstream pathway genes (RAS-MAPK, PI3K-AKT and angiogenesis pathway) showed significant upregulation in Luminal B molecular subtype, lymph node-positive cases and cases with high MVD. The downstream signalling pathways (angiogenesis, RAS-MAPK and PI3K-AKT) were associated high MVD, lymph node metastases, and Her-2 and Luminal B subtype. Since inhibitors of these pathways are commercially available, these can be of therapeutic significance.