Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway.

Breast cancer is the leading cause of cancer deaths for women worldwide. Endocrine therapies represent the cornerstone for hormone-dependent breast cancer treatment. However, in many cases, endocrine resistance is induced with poor prognosis for patients. In the current study, we have developed MCF-7 cell lines resistant to fulvestrant (MCF-7Fulv) and tamoxifen (MCF-7Tam) aiming at investigating mechanisms underlying resistance. Both resistant cell lines exerted lower proliferation capacity in two-dimensional (2-D) cultures but retain estrogen receptor α (ERα) expression and proliferate independent of the presence of estrogens. The established cell lines tend to be more aggressive exhibiting advanced capacity to form colonies, increased expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and heterodimerization of ERBB family receptors and activation of EGFR downstream pathways like MEK/ERK1/2 and PI3K/AKT. Tyrosine kinase inhibitors tested against resistant MCF-7Fulv and MCF-7Tam cells showed moderate efficacy to inhibit cell proliferation, except for lapatinib, which concomitantly inhibits both EGFR and HER2 receptors and strongly reduced cell proliferation. Furthermore, increased autophagy was observed in resistant MCF-7Fulv and MCF-7Tam cells as shown by the presence of autophagosomes and increased Beclin-1 levels. The increased autophagy in resistant cells is not associated with increased apoptosis, suggesting a cytoprotective role for autophagy that may favor cells' survival and aggressiveness. Thus, by exploiting those underlying mechanisms, new targets could be established to overcome endocrine resistance.NEW & NOTEWORTHY The development of resistance to hormone therapy caused by both fulvestrant and tamoxifen promotes autophagy with concomitant apoptosis evasion, rendering cells capable of surviving and growing. The fact that resistance also triggers ERBB family signaling pathways, which are poorly inhibited by tyrosine kinase inhibitors might attribute to cells' aggressiveness. It is obvious that the development of endocrine therapy resistance involves a complex interplay between deregulated ERBB signaling and autophagy that may be considered in clinical practice.

Observation of two-step spin transition in iron(II) 4-amino-1,2,4-triazole based spin crossover nanoparticles.

A synthetically controllable two-step spin transition was observed in iron(II) spin crossover nanoparticles of the dehydrated one-dimensional coordination polymer [Fe(NH2trz)3]Br2 (NH2trz = 4-amino-1,2,4-triazole) using the reverse micellar method. The change from two-step to one-step hysteretic characteristics succeeded by changing the reaction time.

Adhesion strength and anti-tumor agents regulate vinculin of breast cancer cells.

The onset and progression of cancer are strongly associated with the dissipation of adhesion forces between cancer cells, thus facilitating their incessant attachment and detachment from the extracellular matrix (ECM) to move toward metastasis. During this process, cancer cells undergo mechanical stresses and respond to these stresses with membrane deformation while inducing protrusions to invade the surrounding tissues. Cellular response to mechanical forces is inherently related to the reorganization of the cytoskeleton, the dissipation of cell-cell junctions, and the adhesion to the surrounding ECM. Moreover, the role of focal adhesion proteins, and particularly the role of vinculin in cell attachment and detachment during migration, is critical, indicating the tight cell-ECM junctions, which favor or inhibit the metastatic cascade. The biomechanical analysis of these sequences of events may elucidate the tumor progression and the potential of cancer cells for migration and metastasis. In this work, we focused on the evaluation of the spreading rate and the estimation of the adhesion strength between breast cancer cells and ECM prior to and post-treatment with anti-tumor agents. Specifically, different tamoxifen concentrations were used for ER+ breast cancer cells, while even concentrations of trastuzumab and pertuzumab were used for HER2+ cells. Analysis of cell stiffness indicated an increased elastic Young's modulus post-treatment in both MCF-7 and SKBR-3 cells. The results showed that the post-treatment spreading rate was significantly decreased in both types of breast cancer, suggesting a lower metastatic potential. Additionally, treated cells required greater adhesion forces to detach from the ECM, thus preventing detachment events of cancer cells from the ECM, and therefore, the probability of cell motility, migration, and metastasis was confined. Furthermore, post-detachment and post-treatment vinculin levels were increased, indicating tighter cell-ECM junctions, hence limiting the probability of cell detachment and, therefore, cell motility and migration.

Energy Intake and Plasma Adiponectin as Potential Determinants of Lipoprotein-Associated Phospholipase A2 Activity: A Cross-Sectional Study.

Lipoprotein-associated phospholipase A2 (Lp-PLA2 ) is associated with increased risk of cardiovascular diseases (CVD) and type 2 diabetes mellitus. Lp-PLA2 activity is positively associated with male sex, Caucasian race, the presence of metabolic syndrome (MetS) and low-density lipoprotein (LDL)-cholesterol, but it is negatively associated with high-density lipoprotein (HDL)-cholesterol. Associations with other cardiometabolic risk factors, inflammation markers, and lifestyle factors are few or inconsistent. We investigated potential determinants of Lp-PLA2 activity among both nonmodifiable and modifiable CVD risk factors in a middle-aged Greek cohort without overt CVD. Two hundred eighty four subjects (159 men, 53 ± 9 years and 125 women 52 ± 9 years) participated in a cross-sectional study carried out during 2011-2012 in Athens, Attica. Cardiometabolic risk factors, inflammation markers, lifestyle factors, and Lp-PLA2 activity were evaluated with established methods. The American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria were used to define MetS. Lp-PLA2 activity was not associated with MetS, but was associated with MetS components, markers of liver function, and macronutrient intake. Increased total energy intake was associated with increased Lp-PLA2 activity (odds ratio, 95% confidence interval: 1.07, 1.01-1.14 and 1.10, 1.03-1.16 for the 4th and 3rd quartiles, respectively, compared to the 1st quartile) after adjustments for sex, pack-years of smoking, LDL-cholesterol, and statin treatment. Adiponectin tended to be inversely associated with Lp-PLA2 activity (0.91, 0.82-1.00, and 4th versus 1st quartile). Our results suggested that total energy intake and adiponectin levels are potential determinants of Lp-PLA2 activity.

The Impact of Anti-tumor Agents on ER-Positive MCF-7 and HER2-Positive SKBR-3 Breast Cancer Cells Biomechanics.

Studying human cancer from a biomechanical perspective may contribute to pathogenesis understanding which leads to the malignancy. In this study, biomechanics of suspended and adhered breast cancer cells were investigated via the micropipette aspiration method with special emphasis on comparing the cell stiffness and viscoelastic parameters of estrogen receptor positive, ER+, MCF-7 and human epidermal growth factor receptor 2 positive, HER2 +, SKBR-3 cancer cell lines prior to and post treatment with tamoxifen and trastuzumab, respectively. Alterations of mechanical parameters included significant increase in cell stiffness, especially after treatment with trastuzumab and changes in viscoelastic parameters, in both cancer cell lines post treatment. According to immunofluorescence analysis, the raised cell stiffness was corresponded to remodeling of F-actin, which peripherally located in tamoxifen treated and perinuclear accumulated in trastuzumab treated cancer cell cytoskeleton, implying a reduced potential for cell deformation and motility. Additionally, these results were in line with the study of single and collective cell migration through Boyden chamber and wound healing assays respectively, where the potential for migration was significantly decreased after treatment. Consequently, these findings lead to an increased interest in biomechanics of cancer progression after treatment with anti-tumor agents, importantly in understanding the effect of the alterations of mechanical properties upon the possibility for change in metastatic potential.

Integrating Next-Generation Sequencing in the Clinical Pharmacogenomics Workflow.

Pharmacogenomics has been recognized as a fundamental tool in the era of personalized medicine with up to 266 drug labels, approved by major regulatory bodies, currently containing pharmacogenomics information. Next-generation sequencing analysis assumes a critical role in personalized medicine, providing a comprehensive profile of an individual's variome, particularly that of clinical relevance, comprising of pathogenic variants and pharmacogenomic biomarkers. Here, we propose a strategy to integrate next-generation sequencing into the current clinical pharmacogenomics workflow from deep resequencing to pharmacogenomics consultation, according to the existing guidelines and recommendations.

Development of a validated LC-MS/MS method for the in vitro and in vivo quantitation of sunitinib in glioblastoma cells and cancer patients.

Sunitinib is a multi-targeted tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor and is currently being investigated against other forms of malignant tumors. Recently great interest has emerged for the application of sunitinib to glioblastoma treatment. In order to have a method with broad applicability it will be of importance to have access to a method that could be applied both in human plasma and cell uptake studies. No method has been reported thus far for the estimation of sunitinib uptake in glioma cells. We therefore set out to develop a method that could be applied for quantifying sunitinib in human plasma and in cell uptake studies. The method was validated and accredited according to ISO 17025:2005 guideline in human plasma and successfully applied to cancer patient plasma. Also, the method was effectively recruited to establish a protocol for the evaluation of sunitinib accumulation into M095K glioma cells. This method could significantly contribute to developmental phases in repurposing this drug in different cancer types.

Patterns of practice and pharmacoeconomic analysis of the management of patients with metastatic renal cell carcinoma (mRCC) in Greece--the CRISIS study. A retrospective analysis by the Hellenic Genitourinary Cancer Group (HGUCG).

Background:Metastatic RCC (mRCC) treatment has been revolutionized with 11 approved targeted agents. We report patterns of practice, outcomes and pharmacoeconomic analyses after the introduction of targeted therapy. Patients and methods: CRISIS was a retrospective multicenter study of mRCCpatients who received targeted therapy . Results were related to the start of 1st-line therapy, with a cut off at 1 January 2011 in order to depict the impact of increased availability of effective options. Results: 164 patients, were included. 70.1% and 44.5% received 2nd and 3rd-line therapy, respectively. More patients were treated in 2nd-line after 1 January 2011. After a median follow-up of 55.1 months, median progression-free (PFS) and overall survival (OS) were 10.7 (95% confidence intervals [CI]: 8.3-13.7), 7.3 (95% CI: 5.1-8.6), 5.8 (95% CI: 3.8-7.8) and 34 (95% CI: 28.5-39.8), 22.4 (95% CI: 16-32.1), 18.3 (95% CI: 12.4-26.4) months for first, second and third line, respectively. Efficacy of sunitinib and pazopanib in 1st-line were similar. The mean total cost/patient was 35,012.2 Euros (standard deviation [SD]: 28,971.5). Conclusions: Our study confirms previous real-world data suggesting that continuing advances in the treatment of mRCC produce favorable outcomes in everyday practice. Pharmacoeconomic analyses are important for cost-effective utilization of emerging novel therapies.

ILK Expression in Colorectal Cancer Is Associated with EMT, Cancer Stem Cell Markers and Chemoresistance.

BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) are critically implicated in cancer metastasis and chemoresistance. Herein, we investigated integrin-linked kinase (ILK)'s role in human colon cancer (CRC) progression and chemoresistance in relation to EMT and CSC markers. PATIENTS AND METHODS: Expression of ILK, EMT and CSC markers were evaluated by immunohistochemistry in 149 CRC samples. We also generated colon cancer cells resistant to 5-FU and oxaliplatin and studied the effect of ILK inhibition on drug response by MTT assay and on EMT and CSC markers' expression. RESULTS: ILK expression in human CRC correlates with EMT and CSC markers and is associated with metastasis and chemoresistance. ILK inhibition increases sensitivity of resistant cells to 5-FU and oxaliplatin and reduces the levels of EMT and CSC markers in 5-FU resistant cells. CONCLUSION: ILK overexpression in human CRC associates with EMT and CSC traits, contributing to tumor progression and chemoresistance.

Design, synthesis and evaluation of an anthraquinone derivative conjugated to myelin basic protein immunodominant (MBP85-99) epitope: Towards selective immunosuppression.

Anthraquinone type compounds, especially di-substituted amino alkylamino anthraquinones have been widely studied as immunosuppressants. The anthraquinone ring is part of mitoxandrone that has been used for the treatment of multiple sclerosis (MS) and several types of tumors. A desired approach for the treatment of MS would be the immunosuppression and elimination of specific T cells that are responsible for the induction of the disease. Herein, the development of a peptide compound bearing an anthraquinone derivative with the potential to specifically destroy the encephalitogenic T cells responsible for the onset of MS is described. The compound consists of the myelin basic protein (MBP) 85-99 immunodominant epitope (MBP85-99) coupled to an anthraquinone type molecule (AQ) via a disulfide (S-S) and 6 amino hexanoic acid (Ahx) residues (AQ-S-S-(Ahx)6MBP85-99). AQ-S-S-(Ahx)6MBP85-99 could bind to HLA II DRB1*-1501 antigen with reasonable affinity (IC50 of 56 nM) The compound was localized to the nucleus of Jurkat cells (an immortalized line of human T lymphocytes) 10 min after its addition to the medium and resulted in lowered Bcl-2 levels (apoptosis). Entrance of the compound was abolished when cells were pre-treated with cisplatin, an inhibitor of thioredoxin reductase. Accordingly, levels of free thiols were elevated in the culture supernatants of Jurkat cells exposed to N-succinimidyl 3-(2-pyridyldithio) propionate coupled to (Ahx)6MBP85-99 via a disulphide (SPDP-S-S-(Ahx)6MBP85-99) but returned to normal after exposure to cisplatin. These results raise the possibility of AQ-S-S-(Ahx)6MBP85-99 being used as an eliminator of encephalitogenic T cells via implication of the thioredoxin system for the generation of the toxic, thiol-containing moiety (AQ-SH). Future experiments would ideally determine whether SPDP-S-S-(Ahx)6MBP85-99 could incorporate into HLA II DRB1*-1501 tetramers and neutralize encephalitogenic T cell lines sensitized to MBP85-99.

Characterization and Biological Evaluation of Propolis from Poland.

In this study, we assessed the therapeutic potential of propolis from Poland and performed chemical analysis by GC-MS, as well as determined its botanical origin. Chemical constituents typical for bud exudates of Populusnigra (section Aigeiros) were determined, however, glycerol esters of phenolic acids, as well as unusually high amounts of p-coumaric and ferulic acid and their benzyl esters, were also detected. These constituents are characteristic for buds of Populustremula (section Leuce). We also evaluated the antiproliferative effect of propolis extracts against nine human cancer cell lines. Additionally, promising antibacterial activity of the dichloromethane extract (Minimal Inhibitory Concentration MIC values of 0.95-1.24 mg/mL), as well as a moderate antifungal activity (MIC values of 1.25-1.40 mg/mL), was noticed. Propolis from Poland appeared as a rich source of antibacterial and antiproliferative compounds and this confirmed that it is a valuable natural product with the potential to improve human health.

Epidermal growth factor receptor status and Notch inhibition in non-small cell lung cancer cells.

BACKGROUND: Notch may behave as an oncogene or a tumor suppressor gene in lung cancer cells. Notch receptor undergoes cleavage by enzymes, including γ-secretase, generating the active Notch intracellular domain (NICD). The aim of the present study was to investigate the effect of DAPT, a γ-secretase inhibitor, in non-small cell lung cancer (NSCLC) cells, as well as the impact of epidermal growth factor (EGF) that is over-expressed by NSCLC cells, on Notch signaling. H23, A549, H661 and HCC827 human NSCLC cell lines were used, expressing various NICD and EGF receptor (EGFR) protein levels. RESULTS: DAPT decreased the number of H661 cells in a concentration-dependent manner, while it had a small effect on H23 and A549 cells and no effect on HCC827 cells that carry mutated EGFR. Notch inhibition did not affect the stimulatory effect of EGF on cell proliferation, while EGF prevented DAPT-induced NICD decrease in H23 and H661 cells. The type of cell death induced by DAPT seems to depend on the cell type. CONCLUSIONS: Our data indicate that inhibition of Notch cleavage may not affect cell number in the presence of EGFR mutations and that EGFR may affect Notch signalling suggesting that a dual inhibition of these pathways might be promising in NSCLC.

Focal Adhesion Proteins α- and ß-Parvin are Overexpressed in Human Colorectal Cancer and Correlate with Tumor Progression.

This study aims to address the role of focal adhesion proteins α- and ß-parvin in human colorectal carcinoma (CRC). Expression of α- and ß-parvin was examined by immunohistochemistry and real-time RT-PCR in a series of human CRC. Parvins were overexpressed in CRC and their expression correlated significantly with tumor invasion, lymph node metastasis, and disease stage. A significant positive correlation of parvins protein expression with overexpression of integrin-linked kinase, p-AKT, and nuclear ß-catenin, as well as with downregulation of E-cadherin was also observed. In conclusion, overexpression of α- and ß-parvin seems to be implicated in human colorectal cancer progression.

Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach.

Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance.

Regioselective chemical and rapid enzymatic synthesis of a novel redox ­ Antiproliferative molecular hybrid.

Recent science evidenced the interlinkage of oxidative stress and cancer. Due to the inherent complexity of cancer and its accompanying effect of oxidative stress, novel molecules, containing combinatorial functionalities should be targeted. Herein, we synthesized gemcitabine-5'-O-lipoate derived from a regioselective coupling of the chemotherapeutic drug gemcitabine (GEM), a first-line agent for cancer therapy and α-lipoic acid (LA), a potent antioxidant. gemcitabine-5'-O-lipoate was obtained in 4 chemical steps. To avoid the tedious and laborious chemical steps we also utilized biocatalysis using immobilized Candida antarctica lipase B (CALB), and the optimum conditions for the regioselective and one-pot synthesis of gemcitabine-5'-O-lipoate were established by exploiting different solvents (organic solvents and ionic liquids) and enzyme immobilization (acrylic resin and carbon nanotubes). Cytotoxic activity of co-administrating GEM and LA was proven to be synergistic against non-small cell lung cancer cells whereas antagonistic for bladder cancer cells. In contrast, the gemcitabine-5'-O-lipoate hybrid was found to be superior to the parent compounds against both non-small cell lung cancer and bladder cancer cells as also was found to preserve the redox activity of the parent compound LA. The regioselective biotransformation mediated synthesis of the anticancer-antioxidant hybrid illustrates the capacity of biocatalysis to act as an asset in molecular hybridization techniques.

Cell-matrix interactions: focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer.

Proteoglycans are major constituents of extracellular matrices, as well as cell surfaces and basement membranes. They play key roles in supporting the dynamic extracellular matrix by generating complex structural networks with other macromolecules and by regulating cellular phenotypes and signaling. It is becoming evident, however, that proteolytic enzymes are required partners for matrix remodeling and for modulating cell signaling via matrix constituents. Proteinases contribute to all stages of diseases, particularly cancer development and progression, and contextually participate in either the removal of damaged products or in the processing of matrix molecules and signaling receptors. The dynamic interplay between proteoglycans and proteolytic enzymes is a crucial biological step that contributes to the pathophysiology of cancer and inflammation. Moreover, proteoglycans are implicated in the expression and secretion of proteolytic enzymes and often modulate their activities. In this review, we describe the emerging biological roles of proteoglycans and proteinases, with a special emphasis on their complex interplay. We critically evaluate this important proteoglycan-proteinase interactome and discuss future challenges with respect to targeting this axis in the treatment of cancer.

The combination of antitumor drugs, exemestane and erlotinib, induced resistance mechanism in H358 and A549 non-small cell lung cancer (NSCLC) cell lines.

Abstract Context: Estrogens in non-small-cell lung cancer (NSCLC) are important, and their interaction with epidermal growth factor receptor (EGFR) might be crucial. Objective: This study investigates the effect of exemestane, an aromatase inhibitor, and erlotinib, an EGFR inhibitor, on human NSCLC cell lines; H23, H358 and A549. Materials and methods: A cell proliferation assay was used for measuring cell number, apoptosis assay for detecting apoptosis and necrosis and immunoblotting for beclin-1 and Bcl-2 proteins detection. An immunofluorescence assay was used for EGFR localization. A migration assay and zymography were used for cell motility and metalloproteinases (MMPs) expression, respectively. Results: Exemestane, erlotinib or their combination decreased cell proliferation and increased apoptosis. Exemestane's half maximal inhibitory concentration (IC50) was 50 µM for H23 and H358 cells and 20 µM for A549. The IC50 of erlotinib was 25 µM for all cell lines. Apoptosis increase induced by exemestane was 58.0 (H23), 186.3 (H358) and 34.7% (A549) and by erlotinib was 16.7 (H23), 65.3 (H358) and 66.3% (A549). A synergy effect was observed only in H23 cells. Noteworthy, the combination of exemestane and erlotinib decreased beclin-1 protein levels (32.3 ± 19.2%), an indicator of autophagy, in H23 cells. The combination of exemestane and erlotinib partially reversed the EGFR translocation to mitochondria and decreased MMP levels and migration. Discussion and conclusions: The benefit from a dual targeting of aromatase and EGFR seems to be regulated by NSCLC cell content. The diverse responses of cells to agents might be influenced by the dominance of certain molecular pathways.

Serglycin is implicated in the promotion of aggressive phenotype of breast cancer cells.

Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients' material. Moreover, we demonstrate high expression and constitutive secretion of serglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong cytoplasmic staining in these cells, observable at the cell periphery in a thread of filaments near the cell membrane, but also in filopodia-like structures. Serglycin was purified from conditioned medium of MDA-MB-231 cells, and represented the major proteoglycan secreted by these cells, having a molecular size of ~ 250 kDa and carrying chondroitin sulfate side chains, mainly composed of 4-sulfated (~ 87%), 6-sulfated (~ 10%) and non-sulfated (~ 3%) disaccharides. Purified serglycin inhibited early steps of both the classical and the lectin pathways of complement by binding to C1q and mannose-binding lectin. Stable expression of serglycin in less aggressive MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migration and invasion. Interestingly, over-expression of serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellular functions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties. Our findings suggest that serglycin promotes a more aggressive cancer cell phenotype and may protect breast cancer cells from complement attack supporting their survival and expansion.

The exposure of breast cancer cells to fulvestrant and tamoxifen modulates cell migration differently.

There is no doubt that there are increased benefits of hormonal therapy to breast cancer patients; however, current evidence suggests that estrogen receptor (ER) blockage using antiestrogens is associated with a small induction of invasiveness in vitro. The mechanism by which epithelial tumor cells escape from the primary tumor and colonize to a distant site is not entirely understood. This study investigates the effect of two selective antagonists of the ER, Fulvestrant (Fulv) and Tamoxifen (Tam), on the invasive ability of breast cancer cells. We found that 17 ß -estradiol (E2) demonstrated a protective role regarding cell migration and invasion. Fulv did not alter this effect while Tam stimulated active cell migration according to an increase in Snail and a decrease in E-cadherin protein expression. Furthermore, both tested agents increased expression of matrix metalloproteinases (MMPs) and enhanced invasive potential of breast cancer cells. These changes were in line with focal adhesion kinase (FAK) rearrangement. Our data indicate that the anti-estrogens counteracted the protective role of E2 concerning migration and invasion since their effect was not limited to antiproliferative events. Although Fulv caused a less aggressive result compared to Tam, the benefits of hormonal therapy concerning invasion and metastasis yet remain to be investigated.

Comparative study and meta-analysis of meta-analysis studies for the correlation of genomic markers with early cancer detection.

A large number of common disorders, including cancer, have complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. A literature search revealed that even among several meta-analyses, there were ambiguous results and conclusions. In the current study, we conducted a thorough meta-analysis gathering the published meta-analysis studies previously reported to correlate any random effect or predictive value of genome variations in certain genes for various types of cancer. The overall analysis was initially aimed to result in associations (1) among genes which when mutated lead to different types of cancer (e.g. common metabolic pathways) and (2) between groups of genes and types of cancer. We have meta-analysed 150 meta-analysis articles which included 4,474 studies, 2,452,510 cases and 3,091,626 controls (5,544,136 individuals in total) including various racial groups and other population groups (native Americans, Latinos, Aborigines, etc.). Our results were not only consistent with previously published literature but also depicted novel correlations of genes with new cancer types. Our analysis revealed a total of 17 gene-disease pairs that are affected and generated gene/disease clusters, many of which proved to be independent of the criteria used, which suggests that these clusters are biologically meaningful.