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The tumor microenvironment (TME) is constituted by a great diversity of highly dynamic cell populations, each of which contributes ligands, receptors, soluble proteins, mRNAs, and miRNAs, in order to regulate cellular activities within the TME and even promote processes such as angiogenesis or metastasis. Intravasated platelets (PLT) undergo changes in the TME that convert them into tumor-educated platelets (TEP), which supports the development of cancer, angiogenesis, and metastasis through the degranulation and release of biomolecules. Several authors have reported that the deregulation of PF4, VEGF, PDGF, ANG-1, WASF3, LAPTM4B, TPM3, and TAC1 genes participates in breast cancer progression, angiogenesis, and metastasis. The present work aimed to analyze the expression levels of this set of genes in tumor tissues and platelets derived from breast cancer patients by reverse transcription-quantitative polymerase chain reaction (RTqPCR) assays, in order to determine if there was an expression correlation between these sources and to take advantage of the new information to be used in possible diagnosis by liquid biopsy. Data from these assays showed that platelets and breast cancer tumors present similar expression levels of a subset of these genes’ mRNAs, depending on the molecular subtype, comorbidities, and metastasis presence.

Persistent infections with high-risk human papillomavirus (HPV) constitute the main risk factor for cervical cancer development. HPV16 is the most frequent type associated to squamous cell carcinomas (SCC), followed by HPV18. The long control region (LCR) in the HPV genome contains the replication origin and sequences recognized by cellular transcription factors (TFs) controlling viral transcription. Altered expression of E6 and E7 viral oncogenes, modulated by the LCR, causes modifications in cellular pathways such as proliferation, leading to malignant transformation. The aim of this study was to identify specific TFs that could contribute to the modulation of high-risk HPV transcriptional activity, related to the cellular histological origin. We identified sex determining region Y (SRY)-box 2 (SOX2) response elements present in HPV16-LCR. SOX2 binding to the LCR was demonstrated by in vivo and in vitro assays. The overexpression of this TF repressed HPV16-LCR transcriptional activity, as shown through reporter plasmid assays and by the down-regulation of endogenous HPV oncogenes. Site-directed mutagenesis revealed that three putative SOX2 binding sites are involved in the repression of the LCR activity. We propose that SOX2 acts as a transcriptional repressor of HPV16-LCR, decreasing the expression of E6 and E7 oncogenes in a SCC context.

Cytochrome P450 (CYP) epoxygenases and their metabolic products, epoxyeicosatrienoic acids (EETs), have been proposed as important therapeutic targets in the brain. However, CYP expression can be modified by the presence of diverse pro-inflammatory cytokines and the subsequent activation of the NF-κB pathway. It has been indicated that CYP epoxygenases are down-regulated by inflammation in the heart, kidney and liver. However, up to this point, there has been no evidence regarding regulation of CYP epoxygenases during inflammation in the brain. Therefore, in order to explore the effects of inflammation and NF-κB activation in CYP2J3 and CYP2C11 regulation, rat primary astrocytes cultures were treated with LPS with and without IMD-0354 (selective NF-κB inhibitor). Cyp2j3 and Cyp2c11 mRNA expression was determined by qRT-PCR; protein expression was determined by immunofluorescence and by Western Blot and total epoxygenase activity was determined by the quantification of EETs by ELISA. NF-κB binding sites in Cyp2j3 and Cyp2c11 promoter regions were bioinformatically predicted and Electrophoretic Mobility Shift Assays (EMSA) were performed to determine if each hypothetic response element was able to bind NF-κB complexes. Results shown that LPS treatment is able to down-regulate astrocyte CYP2J3 and CYP2C11 mRNA, protein and activity. Additionally, we have identified NK-κB as the transcription factor involved in this regulation.

Curcumin has protective effects against toxic agents and shows preventive properties for various diseases. Particulate material with an aerodynamic diameter of ≤10 μm (PM10) and titanium dioxide nanoparticles (TiO2-NPs) induce endothelial dysfunction and activation. We explored whether curcumin is able to attenuate different events related to endothelial activation. This includes adhesion, expression of adhesion molecules and oxidative stress induced by PM10 and TiO2-NPs. Human umbilical vein endothelial cells (HUVEC) were treated with 1, 10 and 100 μM curcumin for 1 h and then exposed to PM10 at 3 μg/cm2 or TiO2-NPs at 10 μg/cm2. Cell adhesion was evaluated by co-culture with U937 human myelomonocytic cells. Adhesion molecules expression was measured by flow cytometry after 3 or 24 h of exposure. Oxidative stress was determined by 2,7-dichlorodihydrofluorescein (H2DCF) oxidation. PM10 and TiO2-NPs induced the adhesion of U937 cells and the expression of E- and P-selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1). The expression of E- and P-selectins matched the adhesion of monocytes to HUVEC after 3 h. In HUVEC treated with 1 or 10 μM curcumin, the expression of adhesion molecules and monocytes adhesion was significantly diminished. Curcumin also partially reduced the H2DCF oxidation induced by PM10 and TiO2-NPs. Our results suggest an anti-inflammatory and antioxidant role by curcumin attenuating the activation caused on endothelial cells by exposure to particles. Therefore, curcumin could be useful in the treatment of diseases where an inflammatory process and endothelial activation are involved.

Tumor microenvironment is an important promoter of tumorigenesis in all forms of breast cancer and has been associated with the risk of metastasis in the different breast cancer subtypes including the more frequent luminal subtypes that encompass 60% of cancer patients. Adhesive properties of endothelial cells (ECs) are strikingly affected during cancer cell dissemination and are related to functional changes of adhesion receptors. The contribution of tumor secreted factors to tumor‑EC adhesion represents a therapeutic opportunity for breast cancer metastasis. Conditioned medium (CM) of tumor cells can be used as a model to study the role of the secreted molecules to the tumor microenvironment. We explored transcriptomic changes associated to a pro‑adhesive phenotype in primary human umbilical vein endothelial cells (HUVECs) treated with CM of the breast cancer cell line ZR75.30 or with TNF for 3 h. Selected genes were used to validate the microarray through RT‑qPCR. The bioinformatic analysis identified NFκB as the main regulator of the pro-adhesive phenotype and this was confirmed by pharmacological inhibition of NFκB pathway with BAY 11‑7085. The changes induced by ZR75.30‑CM mimic those promoted by TNF and display changes in the expression of genes related to inflammatory response, wound healing, extracellular matrix, cytokines, metabolism and cell communication. Despite the abundance of G‑CSF, IL‑8, IL‑6 and VEGF in the ZR75.30‑CM and the confirmed activation of STAT3 and VEGFR2 pathways, our results suggest dominance of NFκB as a central controller of the transcriptomic response of ECs to breast cancer cells leading to expression of cell adhesion receptors.

Glucocorticoids (GC) are essential steroid hormones for human life. They regulate a series of important processes by binding with three glucocorticoid receptors (GR) and activating genomic and non-genomic pathways. Activated cytoplasmic GR can directly bind DNA and transactivate or transrepress specific genes. Additionally, it can interact with other transcription factors to affect gene expression indirectly. The two membrane GR can interact with mitogen-activated protein (MAP) kinases or activate cAMP and Ca(2+)-dependent pathways, respectively. Glucocorticoids have been widely used as co-treatment of patients with breast cancer (BC) due to reduction of chemotherapy-induced side effects such as nausea, lack of appetite, and inflammation. However, GC may exert a direct effect on tumor response to chemotherapy. In vitro, GC inhibits chemotherapy, radiation and cytokine-induced apoptosis by upregulating antiapoptotic genes and detoxifying proteins. They also upregulate the proto-oncogene c-fms, tumor suppressor gene Nm23, several members of the epidermal growth factor (EGF) signaling pathway and the estrogen sulfotransferase signaling pathway, thus indirectly inhibiting estrogen receptor activation. They inhibit the proangiogenic gene (vascular endothelial growth factor (VEGF); Therefore, they could play a role in reducing angiogenesis. Interestingly, the phosphorylation status of ser-211 in the GR is dependent on the expression of the BRCA1 gene, a tumor suppressor gene that is mutated in the majority of patients with triple negative BC. Some clinical randomized trials have also attempted to address the effect of GC on patients with BC. Thus, in this review we summarize GC mechanisms of action and their participation in several facets of BC.