scholarly journals Persistent organic pollutants and obesity: are they potential mechanisms for breast cancer promotion?

2015 ◽  
Vol 22 (2) ◽  
pp. R69-R86 ◽  
Author(s):  
Denise K Reaves ◽  
Erika Ginsburg ◽  
John J Bang ◽  
Jodie M Fleming
Keyword(s):  
Breast Cancer ◽  
Organic Pollutants ◽  
Persistent Organic Pollutants ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Causal Link ◽  
Model Systems ◽  
Tissue Microenvironment

Dietary ingestion of persistent organic pollutants (POPs) is correlated with the development of obesity. Obesity alters metabolism, induces an inflammatory tissue microenvironment, and is also linked to diabetes and breast cancer risk/promotion of the disease. However, no direct evidence exists with regard to the correlation among all three of these factors (POPs, obesity, and breast cancer). Herein, we present results from current correlative studies indicating a causal link between POP exposure through diet and their bioaccumulation in adipose tissue that promotes the development of obesity and ultimately influences breast cancer development and/or progression. Furthermore, as endocrine disruptors, POPs could interfere with hormonally responsive tissue functions causing dysregulation of hormone signaling and cell function. This review highlights the critical need for advancedin vitroandin vivomodel systems to elucidate the complex relationship among obesity, POPs, and breast cancer, and, more importantly, to delineate their multifaceted molecular, cellular, and biochemical mechanisms. Comprehensivein vitroandin vivostudies directly testing the observed correlations as well as detailing their molecular mechanisms are vital to cancer research and, ultimately, public health.

TMOD-02. GENERATION OF A NOVEL MOUSE MODEL FOR BRAIN TUMORS OF THE DNA METHYLATION CLASS “GBM MYCN”

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi216
Author(s):  
Melanie Schoof ◽  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Sina Al-Kershi ◽  
Ulrich Schüller
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Tumor Development ◽  
Model Systems ◽  
Preclinical Research ◽  
Human Gbm

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.

scholarly journals Protein Kinase C Signaling Mediates a Program of Cell Cycle Withdrawal in the Intestinal Epithelium

2000 ◽  
Vol 151 (4) ◽  
pp. 763-778 ◽  
Author(s):  
Mark R. Frey ◽  
Jennifer A. Clark ◽  
Olga Leontieva ◽  
Joshua M. Uronis ◽  
Adrian R. Black ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Intestinal Epithelium ◽  
Molecular Mechanisms ◽  
Model Systems ◽  
Intestinal Epithelial ◽  
Kinase C

Members of the protein kinase C (PKC) family of signal transduction molecules have been widely implicated in regulation of cell growth and differentiation, although the underlying molecular mechanisms involved remain poorly defined. Using combined in vitro and in vivo intestinal epithelial model systems, we demonstrate that PKC signaling can trigger a coordinated program of molecular events leading to cell cycle withdrawal into G0. PKC activation in the IEC-18 intestinal crypt cell line resulted in rapid downregulation of D-type cyclins and differential induction of p21waf1/cip1 and p27kip1, thus targeting all of the major G1/S cyclin-dependent kinase complexes. These events were associated with coordinated alterations in expression and phosphorylation of the pocket proteins p107, pRb, and p130 that drive cells to exit the cell cycle into G0 as indicated by concomitant downregulation of the DNA licensing factor cdc6. Manipulation of PKC isozyme levels in IEC-18 cells demonstrated that PKCα alone can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells. Notably, analysis of the developmental control of cell cycle regulatory molecules along the crypt–villus axis revealed that PKCα activation is appropriately positioned within intestinal crypts to trigger this program of cell cycle exit–specific events in situ. Together, these data point to PKCα as a key regulator of cell cycle withdrawal in the intestinal epithelium.

scholarly journals Effects of a human-based mixture of persistent organic pollutants on the in vivo exposed cerebellum and cerebellar neuronal cultures exposed in vitro

2021 ◽  
Vol 146 ◽  
pp. 106240
Author(s):  
Hanne Friis Berntsen ◽  
Nur Duale ◽  
Cesilie Granum Bjørklund ◽  
Oscar Daniel Rangel-Huerta ◽  
Kine Dyrberg ◽  
...  
Keyword(s):  
Organic Pollutants ◽  
Persistent Organic Pollutants ◽  
Neuronal Cultures

scholarly journals Hydrophobized Reversed-Phase Adsorbent for Protection of Dairy Cattle against Lipophilic Toxins from Diet. Efficiensy In Vitro and In Vivo

Toxins ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 256
Author(s):  
Alexander Sotnichenko ◽  
Evgeny Pantsov ◽  
Dmitry Shinkarev ◽  
Victor Okhanov
Keyword(s):  
Dairy Cattle ◽  
Organic Pollutants ◽  
Persistent Organic Pollutants ◽  
Polyaromatic Hydrocarbons ◽  
Reversed Phase ◽  
Chemical Pollution ◽  
Lipophilic Toxins ◽  
Cattle Feeds

The steady growth of inflammatory diseases of the udder in dairy cattle forces us to look for the causes of this phenomenon in the context of growing chemical pollution of the environment and feeds. Within the framework of this concept, an analysis was made of the polarity level of the three toxic impurity groups, which are commonly present in dairy cattle feeds. These impurities are presented by mycotoxins, polyaromatic hydrocarbons (PAH) and persistent organic pollutants (POP). It has been determined that 46% of studied mycotoxins (n = 1500) and 100% of studied polyaromatic hydrocarbons (n = 45) and persistent organic pollutants (n = 55) are lipophilic compounds, prone to bioaccumulation. A comparative evaluation of the sorption capacity of four adsorbents of a different nature and polarity with respect to the simplest PAH, naphthalene and lipophilic estrogenic mycotoxin, zearalenone in vitro has been carried out. The highest efficiency in these experiments was demonstrated by the reversed-phase polyoctylated polysilicate hydrogel (POPSH). The use of POPSH in a herd of lactating cows significantly reduced the transfer of aldrin, dieldrin and heptachlor, typical POPs from the “dirty dozen”, to the milk. The relevance of protecting the main functional systems of animals from the damaging effects of lipophilic toxins from feeds using non-polar adsorbents, and the concept of evaluating the effectiveness of various feed adsorbents for dairy cattle by their influence on the somatic cell count in the collected milk are discussed.

scholarly journals Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast caner cells and osteoclasts

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Ming-Xuan Feng ◽  
Jian-Xin Hong ◽  
Qiang Wang ◽  
Yong-Yong Fan ◽  
Chi-Ting Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Resorption ◽  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Metastatic Breast ◽  
Osteoclast Formation ◽  
Migration And Invasion ◽  
Titanium Particle

Abstract Bone is the most common site of distant relapse in breast cancer, leading to severe complications which dramatically affect the patients’ quality of life. It is believed that the crosstalk between metastatic breast cancer cells and osteoclasts is critical for breast cancer-induced osteolysis. In this study, the effects of dihydroartemisinin (DHA) on osteoclast formation, bone resorption, osteoblast differentiation and mineralization were initially assessed in vitro, followed by further investigation in a titanium-particle-induced osteolysis model in vivo. Based on the proved inhibitory effect of DHA on osteolysis, DHA was further applied to MDA-MB-231 breast cancer-induced mouse osteolysis model, with the underlying molecular mechanisms further investigated. Here, we verified for the first time that DHA suppressed osteoclast differentiation, F-actin ring formation and bone resorption through suppressing AKT/SRC pathways, leading to the preventive effect of DHA on titanium-particle-induced osteolysis without affecting osteoblast function. More importantly, we demonstrated that DHA inhibited breast tumor-induced osteolysis through inhibiting the proliferation, migration and invasion of MDA-MB-231 cells via modulating AKT signaling pathway. In conclusion, DHA effectively inhibited osteoclastogenesis and prevented breast cancer-induced osteolysis.

scholarly journals Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish

2021 ◽  
Vol 22 (17) ◽  
pp. 9279
Author(s):  
Inés Martínez-Pena ◽  
Pablo Hurtado ◽  
Nuria Carmona-Ule ◽  
Carmen Abuín ◽  
Ana Belén Dávila-Ibáñez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Molecular Mechanisms ◽  
Zebrafish Embryo ◽  
Cancer Metastasis ◽  
Fluid Shear Stress ◽  
In Vivo Models

Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.

scholarly journals CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 129
Author(s):  
Huinan Qu ◽  
Da Qi ◽  
Xinqi Wang ◽  
Yuan Dong ◽  
Qiu Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Suppressor Gene ◽  
Binding Motif ◽  
Cancer Proliferation ◽  
In Vivo Experiments

Claudin 6 (CLDN6) was found to be a breast cancer suppressor gene, which is lowly expressed in breast cancer and inhibits breast cancer cell proliferation upon overexpression. However, the mechanism by which CLDN6 inhibits breast cancer proliferation is unclear. Here, we investigated this issue and elucidated the molecular mechanisms by which CLDN6 inhibits breast cancer proliferation. First, we verified that CLDN6 was lowly expressed in breast cancer tissues and that patients with lower CLDN6 expression had a worse prognosis. Next, we confirmed that CLDN6 inhibited breast cancer proliferation through in vitro and in vivo experiments. As for the mechanism, we found that CLDN6 inhibited c–MYC–mediated aerobic glycolysis based on a metabolomic analysis of CLDN6 affecting cellular lactate levels. CLDN6 interacted with a transcriptional co–activator with PDZ-binding motif (TAZ) and reduced the level of TAZ, thereby suppressing c–MYC transcription, which led to a reduction in glucose uptake and lactate production. Considered together, our results suggested that CLDN6 suppressed c–MYC–mediated aerobic glycolysis to inhibit the proliferation of breast cancer by TAZ, which indicated that CLDN6 acted as a novel regulator of aerobic glycolysis and provided a theoretical basis for CLDN6 as a biomarker of progression in breast cancer.

scholarly journals Targeting PML in triple negative breast cancer elicits growth suppression and senescence

2019 ◽  
Vol 27 (4) ◽  
pp. 1186-1199 ◽  
Author(s):  
Leire Arreal ◽  
Marco Piva ◽  
Sonia Fernández ◽  
Ajinkya Revandkar ◽  
Ariane Schaub- Clerigué ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Function ◽  
Breast Cancer Subtype ◽  
Growth Arrest ◽  
Promoter Regions

Abstract Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.

The design of an environmentally relevant mixture of persistent organic pollutants for use in in vivo and in vitro studies

2017 ◽  
Vol 80 (16-18) ◽  
pp. 1002-1016 ◽  
Author(s):  
Hanne Friis Berntsen ◽  
Vidar Berg ◽  
Cathrine Thomsen ◽  
Erik Ropstad ◽  
Karin Elisabeth Zimmer
Keyword(s):  
Organic Pollutants ◽  
Persistent Organic Pollutants ◽  
In Vitro Studies
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