Comparative Analysis of Breast Cancer Metabolomes Highlights Fascin's Central Role in Regulating Key Pathways Related to Disease Progression.

Omics technologies provide useful tools for the identification of novel biomarkers in many diseases, including breast cancer, which is the most diagnosed cancer in women worldwide. We and others have reported a central role for the actin-bundling protein (fascin) in regulating breast cancer disease progression at different levels. However, whether fascin expression promotes metabolic molecules that could predict disease progression has not been fully elucidated.

Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity.

A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene.

PD-L1 intrinsically promotes the proliferation of breast cancer cells through the SKP2-p27/p21 axis.

Background: PD-L1 intrinsically promotes tumor progression through multiple mechanisms, which potentially leads to resistance to anti-PD-1/PD-L1 therapies. The intrinsic effect of PD-L1 on breast cancer (BC) cell proliferation has not been fully elucidated.

Methods: we used proteomics, gene expression knockdown (KD), quantitative immunofluorescence (qIF), western blots, functional assays including colony-forming assay (CFA) and real-time cell analyzer (RTCA), and in vivo data using immunohistochemistry in breast cancer patients.

A unique STK4 mutation truncating only the C-terminal SARAH domain results in a mild clinical phenotype despite severe T cell lymphopenia: Case report.

Mutations in STK4 (MST1) are implicated in a form of autosomal recessive combined immunodeficiency, resulting in recurrent infections (especially Epstein-Barr virus viremia), autoimmunity, and cardiac malformations. Here we report a patient with an atypically mild presentation of this disease, initially presenting with severe T cell lymphopenia (< 500 per mm) and intermittent neutropenia, but now surviving well on immunoglobulins and prophylactic antibacterial treatment. She harbors a unique STK4 mutation that lies further downstream than all others reported to date.

Metabolic Alteration of MCF-7 Cells upon Indirect Exposure to Secretome: A Model of Studying the Microbiota Effect on Human Breast Tissue.

According to studies, the microbiome may contribute to the emergence and spread of breast cancer. is one of the Enterobacteriaceae family recently found to be present as part of the breast tissue microbiota. In this study, we focused on the effect of secretome free of cells on MCF-7 metabolism.

β-catenin attenuation leads to up-regulation of activating NKG2D ligands and tumor regression in -driven thyroid cancer cells.

Introduction: mutations frequently occur in papillary thyroid cancer (PTC). β-catenin, encoded by , is a key downstream component of the canonical Wnt signaling pathway and is often overexpressed in PTC. -driven PTC tumors rely on Wnt/β-catenin signaling to sustain growth and progression.

Secretome Metabolically Modulates MDA-MB-231 Breast Cancer Cells' Energy Metabolism.

Breast cancer (BC) is commonly diagnosed in women. BC cells are associated with altered metabolism, which is essential to support their energetic requirements, cellular proliferation, and continuous survival. The altered metabolism of BC cells is a result of the genetic abnormalities of BC cells.

Reciprocal interplays between MicroRNAs and pluripotency transcription factors in dictating stemness features in human cancers.

The interplay between microRNAs (miRNAs) and pluripotency transcription factors (TFs) orchestrates the acquisition of cancer stem cell (CSC) features during the course of malignant transformation, rendering them essential cancer cell dependencies and therapeutic vulnerabilities. In this review, we discuss emerging themes in tumor heterogeneity, including the clonal evolution and the CSC models and their implications in resistance to cancer therapies, and then provide thorough coverage on the roles played by key TFs in maintaining normal and malignant stem cell pluripotency and plasticity. In addition, we discuss the reciprocal interactions between miRNAs and MYC, OCT4, NANOG, SOX2, and KLF4 pluripotency TFs and their contributions to tumorigenesis.

Fascin is essential for mammary gland lactogenesis.

Fascin expression has commonly been observed in certain subtypes of breast cancer, where its expression is associated with poor clinical outcome. However, its role in normal mammary gland development has not been elucidated. Here, we used a fascin knockout mouse model to assess its role in normal mammary gland morphogenesis and lactation.

Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression.

Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies for TNBC requires better understanding of biology and signaling networks that promote disease progression.

β-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAF-Driven Thyroid Cancer Animal Model.

mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin () is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. -driven tumors have been speculated to rely on Wnt/β-catenin signaling to sustain its growth, although many details remain to be elucidated.

Higher PD-L1 Immunohistochemical Detection Signal in Frozen Compared to Matched Paraffin-Embedded Formalin-Fixed Tissues.

Purpose: Response to anti-PD-L1/PD-1 immunotherapy correlates with PD-L1 expression in breast cancer. However, the prevalence of PD-L1 positive breast cancer is variable, which could be due to differences in the population/cohort of patients tested or the preservation/detection technology used. To investigate this variability, we examined the effect of two tissue preservation methods on PD-L1 immunohistochemical detection in breast cancer.

Fascin Activates β-Catenin Signaling and Promotes Breast Cancer Stem Cell Function Mainly Through Focal Adhesion Kinase (FAK): Relation With Disease Progression.

Cancer stem cells (CSCs), a rare population of tumor cells with high self-renewability potential, have gained increasing attention due to their contribution to chemoresistance and metastasis. We have previously demonstrated a critical role for the actin-bundling protein (fascin) in mediating breast cancer chemoresistance through activation of focal adhesion kinase (FAK). The latter is known to trigger the β-catenin signaling pathway.

PD-L1 is overexpressed on breast cancer stem cells through notch3/mTOR axis.

The T-cell inhibitory molecule PD-L1 is expressed on a fraction of breast cancer cells. The distribution of PD-L1 on the different subpopulations of breast cancer cells is not well-defined. Our aim was to study the expression level of PD-L1 on breast cancer stem-like (CSC-like) cells and their differentiated-like counterparts.

Differential expression of CCR2 and CXCR1 on CD16 monocyte subsets is associated with asthma severity.

Background: Monocytes play an important role in immune and inflammatory diseases and monocyte subsets are predictors of disease in certain conditions. Expression of the chemokine receptors, CCR2 and CXCR1 on monocyte subsets relates to their function and can be used in their characterization. Our objective was to determine whether CD14, CD16, CCR2 and CXCR1 on monocyte subsets are potential indicators of asthma severity.

Antibody-drug conjugate T-DM1 treatment for HER2+ breast cancer induces ROR1 and confers resistance through activation of Hippo transcriptional coactivator YAP1.

Background: A newly developed drug trastuzumab emtansine (T-DM1) has improved the survival of breast cancer (BC) patients. Despite an impressive initial clinical response, a subgroup of patient develop resistance and present therapeutic challenges. The underlying resistance mechanisms are not fully investigated.

β1 Integrin is essential for fascin-mediated breast cancer stem cell function and disease progression.

Breast cancer remains the second cause of tumor-related mortality in women worldwide mainly due to chemoresistance and metastasis. The chemoresistance and metastasis are attributed to a rare subpopulation with enriched stem-like characteristics, thus called Cancer Stem Cells (CSCs). We have previously reported aberrant expression of the actin-bundling protein (fascin) in breast cancer cells, which enhances their chemoresistance, metastasis and enriches CSC population.

Gene expression data analysis identifies multiple deregulated pathways in patients with asthma.

Asthma is a chronic inflammatory disorder associated with airway hyper-responsiveness. Although a number of studies have investigated asthma at the molecular level, the molecular immune signatures associated with asthma severity or with the response to corticosteroids are still being unraveled. The present study integrated four asthma-related gene expression datasets from the Gene Expression Omnibus and identified immune-gene signatures associated with asthma development, severity, or response to treatment.

PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation.

The expression of PD-L1 in breast cancer is associated with estrogen receptor negativity, chemoresistance and epithelial-to-mesenchymal transition (EMT), all of which are common features of a highly tumorigenic subpopulation of cancer cells termed cancer stem cells (CSCs). Hitherto, the expression and intrinsic role of PD-L1 in the dynamics of breast CSCs has not been investigated. To address this issue, we used transcriptomic datasets, proteomics and several in vitro and in vivo assays.

Fascin Is Critical for the Maintenance of Breast Cancer Stem Cell Pool Predominantly via the Activation of the Notch Self-Renewal Pathway.

An emerging dogma shows that tumors are initiated and maintained by a subpopulation of cancer cells that hijack some stem cell features and thus referred to as "cancer stem cells" (CSCs). The exact mechanism that regulates the maintenance of CSC pool remains largely unknown. Fascin is an actin-bundling protein that we have previously demonstrated to be a major regulator of breast cancer chemoresistance and metastasis, two cardinal features of CSCs.

Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells.

Background: The T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well-identified.

Methods: We have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections.

Differential marker expression by cultures rich in mesenchymal stem cells.

Background: Mesenchymal stem cells have properties that make them amenable to therapeutic use. However, the acceptance of mesenchymal stem cells in clinical practice requires standardized techniques for their specific isolation. To date, there are no conclusive marker (s) for the exclusive isolation of mesenchymal stem cells.

Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules.

The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined.

Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule.

Introduction: B7-H1 (PD-L1, CD274) is a T cell inhibitory molecule expressed in many types of cancer, leading to immune escape of tumor cells. Indeed, in previous reports we have shown an association of B7-H1 expression with high-risk breast cancer patients.

Methods: In the current study, we used immunohistochemistry, immunofluorescence and Western blot techniques to investigate the effect of neoadjuvant chemotherapy on the expression of B7-H1 in breast cancer cells.