Deciphering Potential Role of Hippo Signaling Pathway in Breast Cancer: A Comprehensive Review.

Breast cancer is a heterogeneous disease and a leading malignancy around the world. It is a vital cause of untimely mortality among women. Drug resistance is the major challenge for effective cancer therapeutics. In contrast, cancer stem cells (CSCs) are one of the reasons for drug resistance, tumor progression, and metastasis. The small population of CSCs present in each tumor has the ability of self-renewal, differentiation, and tumorigenicity. CSCs are often identified and enriched using a variety of cell surface markers (CD44, CD24, CD133, ABCG2, CD49f, LGR5, SSEA-3, CD70) that exert their functions by different regulatory networks, i.e., Notch, Wnt/ß-catenin, hedgehog (Hh), and Hippo signaling pathways. Particularly the Hippo signaling pathway is the emerging and very less explored cancer stem cell pathway. Here, in this review, the Hippo signaling molecules are elaborated with respect to their ability of stemness as epigenetic modulators and how these molecules can be targeted for better cancer treatment and to overcome drug resistance.

Significance of metastamiR-10b in breast cancer therapeutics.

BACKGROUND: Breast cancer is a fatal disease and a major reason of cancer associated death in females. Many factors along with miRNA are responsible for the development and the progression of the disease. The miRNA plays a very crucial role in the regulation of the genes. MicroRNAs are of three major types-oncomiRs, tumor suppressive miRNAs, and metastamiRs. MAIN BODY: MicoRNA-10b is a prometastatic microRNA targeting various genes that facilitates multiple outcomes such as metastasis, increased capacity for invasion, proliferation and migration, increased epithelial-mesenchymal transformation, angiogenesis, and therefore exhibits worse clinical outcomes. It is found to be upregulated in various malignancies and is thus to be considered as the possible therapeutic candidate. CONCLUSION: The therapeutic delivery of miR-10b antagonists (antagomiRs) and/or knockdown of miRNA is beneficial in reducing tumor growth. Additionally, combination therapy which includes antisense oligonucleotides using miR-10b can function as an effective approach to tumor regression and drug resistance reversal.

Identification of Natural Compounds to Inhibit Sonic Hedgehog Pathway in Oral Cancer.

BACKGROUND: Conventional treatment resistance remains a significant problem in cancer care. Cancer stem cells might play a major role in treatment resistance, and as a result, basic stem cell pathways are instrumental in cancer. Sonic Hedgehog signaling has not been widely studied in oral cancer, and being one of the major cancer stem cell pathways, targeting it with natural compounds could open many opportunities in the treatment scenario. OBJECTIVE: The objective of the study was to identify the role of various natural compounds as an anti-cancer agent for oral cancer by targeting the Hedgehog signaling pathway. METHODS: The selection of natural compounds were identified through literature review and NPACT database. The protein (3M1N and 3MXW) and ligand molecules were retrieved through the PDB and PubChem database. To carry out docking experiments, the AutoDock 4.2 program was used to study the interaction between the identified protein and ligand. RESULTS: Among the 13 identified natural compounds, the top three were selected based on their binding energy. The higher the binding energy on the negative side, the better the interaction formed between protein and ligand. The natural compound showing best results with 3M1N protein were Butein, Biochanin-A, and Curcumin, whereas, with 3MXW, Zerumbone, Curcumin, and Butein were identified. CONCLUSION: The identified natural compounds have shown better binding energy to bind the Hh ligands in the absence/ presence of a known Sonic Hedgehog inhibitor. Based on the results, natural compounds can be utilized in the current treatment modality for oral cancer either as an individual anti-cancer agent or in combination with the known Sonic Hedgehog inhibitor to curb the increasing incidence rate. Yet, in-vitro evidence in lab setup is required.

EGFR Mutation Analysis in Non-small Cell Lung Carcinoma Patients: A Liquid Biopsy Approach.

In the era of the targeted therapy identification of EGFR mutation detection in lung cancer is extremely helpful to predict the treatment efficacy of EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, the inadequacy and quality of the biopsy samples are the major obstacles in molecular testing of EGFR mutation in lung cancer. To address this issue, the present study intended to use liquid biopsy as the non-invasive method for EGFR mutation detection. A total of 31 patients with an advanced stage of lung cancer were enrolled in the study from which cell-free DNA (cfDNA) and FFPE tissue DNA was extracted. Extracted DNA samples were analyzed for further EGFR exon specific mutation analysis by ARMS-PCR. Data were analyzed statistically using SPSS software. In cfDNA samples, the prevalence of wild type EGFR was 48% while the prevalence of TKI resistant and TKI sensitive mutations were 3%. Conversely, in tissue DNA samples, the prevalence of wild type, TKI sensitive and TKI resistant mutations were 48%, 19%, and 3%, respectively. The overall concordance of EGFR mutation between cfDNA and tissue DNA was 83%. McNemar's test revealed that there was no significant difference between EGFR expression of cfDNA and tissue DNA samples. Additionally, the significant-high incidence of TKI resistant mutations was observed in tobacco habituates, indicating the role of carcinogens present in the tobacco in developing resistant mutations. In conclusion, our data suggest that evaluation of EGFR mutation from cfDNA samples is practicable as a non-invasive tool in patients with advanced-stage of lung cancer.

Putative stemness markers octamer-binding transcription factor 4, sex-determining region Y-box 2, and NANOG in non-small cell lung carcinoma: A clinicopathological association.

BACKGROUND: The promising improvement in the clinical outcome of lung cancer can be possibly achieved by identification of the molecular events that underlie its pathogenesis. Cancer stem cell (CSC) being one of the subsets of tumor majorly participates in drug resistance and treatment failure because of the moderate cell cycle, lower proliferation, and increased expression of DNA repair and anti-apoptosis genes. Although many putative CSC markers exist, a precise characterization for non-small cell lung cancer is of utmost importance due to increased mortality rate and lack of targeted therapies. Hence, the article focuses on the expression of stemness-associated markers, namely octamer-binding transcription factor 4 (OCT4), NANOG, and sex-determining region Y-box 2 (SOX2) in non-small cell lung cancer (NSCLC) patients. METHODS: The expression of OCT4, NANOG, and SOX2 were evaluated in 32 histopathologically confirmed NSCLC tissues using real-time polymerase chain reaction. The obtained expression was correlated with clinical and pathological manifestations using the statistical test such as Student's t-test and Pearson correlation in varied statistical software. RESULTS: Results showed a significantly higher expression of OCT4 and NANOG compared to SOX2 in the tumor tissues. When the expression of these markers was correlated with the clinical parameters, higher expression was seen in males, patients with age above 60 years, and in adenocarcinoma subtype. In correlation with the habit, higher expression of OCT4 and SOX2 was observed in habituated patients. Expression of NANOG and OCT4 was higher even in patients with poor differentiation. CONCLUSION: The expression and prognostic significance of CSC markers obviously vary depending on histological NSCLC subtype. Importantly, our findings suggest that OCT4, SOX2, and NANOG network together may be promising for ongoing targeted therapies in specific NSCLC subgroups.

Role of epithelial - Stromal interaction protein-1 expression in breast cancer.

BACKGROUND AND AIMS: Epithelial stromal interaction protein-1 (EPSTI-1) is originally identified as stromal-fibroblast - induced gene in breast cancer. It was found to be involved in promotion of EMT, breast cancer invasion, metastasis and anchorage-independent growth in vitro. Strong expression was observed in various tissues as well as higher expression was observed in invasive breast cancer compared to normal breast. EPSTI-1 expression was evaluated from 106 pre-therapeutic breast cancer patients. EPSTI-1 expression was correlated with known clinico-pathological parameters of breast cancer to explore its role in breast carcinogenesis. SUBJECTS AND METHODS: EPSTI-1 expression was analyzed from the collected synchronous tissues [tumors, Malignant Lymph nodes (LN) and adjacent normal tissues (ANT)] of breast carcinoma patients (N = 106). The statistical correlation was performed using SPSS 16.0. RESULTS: In this study EPSTI-1 was significantly higher in LN compared to tumors (P < 0.001), and in tumors compared to ANT (P < 0.01) which is also reflected in ROC curve analysis (P < 0.0001). Further the small tumor size, stage I, grade I and tumors without stromal involvement exhibited significant lower expression compared to their counter parts. CONCLUSION: EPSTI-1 may have significant role in epithelial stromal interaction and disease extension. Moreover, it may be responsible for aggressive tumor behavior and involved in metastatic process which needs to be validated in larger cohort.

A Prognostic and Predictive Study of BCR-ABL Expression Based on Characterization of Fusion Transcripts.

BCR-ABL translocation is a key hallmark of chronic myeloid leukemia (CML). The chemistry involves transcription of a novel 8.5 kb mRNA with a b3a2 and/ or b2a2 junction. Though there is an improvement in survival using the TKIs, there are causes for the treatment failures. Thus, the study focuses on the causes underlying the failed response. This study comprises BCR-ABL expression in correlation with age, gender and transcript type and disease monitoring in follow-up samples. Eighty-seven chronic phase CML patients were enrolled in the study. Out of these 24 patients were followed further. Quantitative Real time PCR was performed to assess the BCR-ABL expression followed by gel electrophoresis of PCR products. The results were expressed as CN/µg RNA. The results obtained were correlated with SPSS 16.0 software. We found three different types of the expression that includes b2a2, b3a2 and co-expression (b2a2 + b3a2). Higher incidence of b2a2 with a relatively equal incidence of co-expression was observed. The BCR-ABL expression was higher in males, in young patients and in those exhibiting co-expression of the transcripts. Greater relapse was seen in females and in older patients. The patients with co-expression of transcripts exhibited the highest expression; however these patients showed the best treatment response suggest the co-expression is the favourable parameter for CML patients. The transcript type and BCR-ABL expression are well correlated and hence can be considered as a prognostic as well as the predictive indicator considering the BCR-ABL expression for CML patients.

Breast cancer: Role of IGF-1 and IGFBP-3 expression in prognostication.

Deregulation of Insulin like growth factors (IGF) is an>important determinant of breast carcinogenesis. Circulatory IGF-1 (potent breast mitogen) and IGFBP-3 (its regulator) are exteisively evaluated; few studies report transcript copy numbers.(CN) from ex-vivo samples. This study from 106 patients evaluated mRNA expression (qRT-PCR CN) of IGF-1 and IGFBP-3 for prognostic and predictive utility from tumor, adjacent normal tissues (ANT) and lymph nodes. The differences in.IGF-1 and IGFBP-3 mRNA levels (CN/µg RNA) were juxtaposed to clinical and pathologic variables and survival. Tumors expressed lower IGF-1 and higher IGFBP-3 as compared to ANT. Both transcript levels decreased with increasing age. Primary tumors with nodal involvement, Invasive Lobular carcinoma (ILC) histology and stromal involvement showed increased transcript levels than their respective counterparts. Moreover, surviving patients showing no relapse had higher expression of both molecules. Early stage and necrosed tumors expressed higher IGFBP-3 while a trend of lower expression was seen as tumor grade advanced. IGF-1 expression was inversely correlated to stage, histologic grade and. Significantly different Relapse Free Survival (RFS) was seen with IGFBP-3 up-/down-regulation considering progesterone receptor (PR) status but not estrogen receptor (ER) and HER-2 while the Overall Survival (OS) was similar for both these molecules. We conclude that expression of these molecules may aid prognostication and success of anti IGF-1 strategies.