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Cancer Research Aug 2021Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we...
Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. SIGNIFICANCE: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G-M checkpoint and proliferative signaling.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Autoantigens; Breast Neoplasms; Carcinogenesis; Carrier Proteins; Cell Cycle; Cell Line, Tumor; Cell Proliferation; DNA Damage; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Knockout; Mice, Transgenic; Mitosis; Mutation; Nuclear Proteins; Proteome; Recombination, Genetic; Signal Transduction
PubMed: 34145035
DOI: 10.1158/0008-5472.CAN-20-3651 -
Nutrients May 2021The purpose of this work was to evaluate the effect of the nanosized or microsized zinc (Zn) particles on fatty acid profile, enzyme activity and the level of...
The purpose of this work was to evaluate the effect of the nanosized or microsized zinc (Zn) particles on fatty acid profile, enzyme activity and the level of cholesterol, squalene and oxysterols in rats with breast cancer. Rats (female, = 24) were divided into the following groups: control, and two test groups, whose diets were enriched with either Zn microparticles (342 nm) or Zn nanoparticles (99 nm). All rats were treated twice with the carcinogenic agent; 7,12-dimethylbenz[a]anthracene. In rats whose diet was enriched with zinc (especially in the form of nanoparticles), the number and sizes of tumors were lower. Diet supplementation also significantly reduced the cholesterol ( = 0.027) and COPs (cholesterol oxidation products) levels ( = 0.011) in rats serum. Enriching the diet with Zn microparticles decreased the Δ6-desaturase activity ( < 0.001). Zn influences fatty acids' profile in rats' serum as well as inhibiting desaturating enzymes. A reduced amount of pro-inflammatory arachidonic acid derivatives may be the expected effect.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Breast Neoplasms; Cholesterol; Cholesterol Oxidase; Dietary Supplements; Disease Models, Animal; Fatty Acids; Female; Food, Fortified; Linoleoyl-CoA Desaturase; Metal Nanoparticles; Particle Size; Rats; Tumor Burden; Zinc
PubMed: 34066470
DOI: 10.3390/nu13051563 -
DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A.The Journal of Cell Biology Aug 2021Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of...
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; CCAAT-Enhancer-Binding Protein-beta; Cell Cycle Checkpoints; Cell Proliferation; Cellular Senescence; DNA Methylation; Epigenesis, Genetic; Female; Fibroblasts; HEK293 Cells; Histone-Lysine N-Methyltransferase; Histones; Humans; Interleukin-1alpha; Membrane Proteins; Mice; Microscopy, Fluorescence; Papilloma; Phenotype; Secretory Pathway; Skin Neoplasms; Tetradecanoylphorbol Acetate
PubMed: 34037658
DOI: 10.1083/jcb.202008101 -
Investigational New Drugs Dec 2021Pancreatic cancer is among the most refractory malignancies with poor prognosis. Thus, preventive approaches, in addition to the development of novel therapeutic...
Pancreatic cancer is among the most refractory malignancies with poor prognosis. Thus, preventive approaches, in addition to the development of novel therapeutic strategies are essential for this type of cancer. KRAS mutations occur very early in the development of pancreatic cancers and could be targeted for its prevention, yet specific inhibitors for mutated KRAS are lacking. Accordingly, Glutathione-S Transferase p1 (GSTP1), which we recently found to be an autocrine stimulator of mutated KRAS signaling, is predicted to be an alternative target for chemoprevention of pancreatic cancer. In this study, chemopreventive effects of O-Hexadecyl-γ-glutamyl-S-benzyl-cysteinyl-D-phenyl glycine-Ethylester (HGBPE), which we previously synthesized to inhibit GSTP1 activity, was analyzed for its effect on the prevention of a rat pancreatic carcinogenesis model induced by 7,12-dimethyl-benzanthracene (DMBA). Rats administered with DMBA were grouped into five cohorts. In the treated group I, which was treated neither with HGBPE nor vehicle, sequential appearance of precancerous lesions, ductal complexes, and adenocarcinoma was confirmed as previously reported. We also confirmed in this group that mutations of KRAS and expression of GSTP1 simultaneously occurred in the ductal complex. To rats of groups II and IV, HGBPE was administered, and vehicle to those of group III and V. In groups of II and IV, the incidence of both ductal complex and adenocarcinoma were significantly lower than those in groups III and V. These data clearly suggest the efficacy of HGBP as a potential chemopreventive agent for pancreatic cancer.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Disease Models, Animal; Glutathione S-Transferase pi; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 34031785
DOI: 10.1007/s10637-021-01129-y -
Evaluation of the chemopreventive effects of Hypericum perforatum L on DMBA-applied rat oral mucosa.Archives of Oral Biology Jul 2021Hypericum perforatum L also known as St. John's wort is known to have many beneficial properties for the organism including its antioxidant and anticancer activities. It...
OBJECTIVE
Hypericum perforatum L also known as St. John's wort is known to have many beneficial properties for the organism including its antioxidant and anticancer activities. It is also known to have shown antiproliferative and cytotoxic effects against various cancer cell lines. The purpose of this study was to investigate the effects of Hypericum perforatum L on 7,12-dimethylbenz(a)anthracene-induced rat oral squamous cell carcinoma model.
DESIGN
The in vitro antioxidant properties of Hypericum perforatum L was determined and an extract was prepared. Thirty Wistar male rats were divided randomly into 4 groups (Control group, DMBA group, HP + DMBA group, HP group). The antioxidant defense mechanisms in tissue and blood samples were evaluated biochemically and immunohistochemically, the carcinomatous changes in connective tissue were investigated immunohistochemically and epithelial changes in the tissue samples were evaluated histopathologically.
RESULTS
The extract revealed inhibitory effects on some antioxidant enzymes (catalase, glutathione peroxidase). Immunohistochemical evaluations revealed no invasive changes in the connective tissue. Hypericum perforatum L demonstrated chemopreventive effects although it did not prevent carcinomatous changes altogether.
CONCLUSIONS
Hypericum perforatum L is a promising chemopreventive agent and further studies are needed in order to evaluate the full potential of this plant.
Topics: Animals; Carcinoma, Squamous Cell; Hypericum; Male; Mouth Mucosa; Mouth Neoplasms; Plant Extracts; Rats; Rats, Wistar
PubMed: 33964648
DOI: 10.1016/j.archoralbio.2021.105139 -
Veterinary Medicine and Science Sep 2021Newly, chemo-preventive technique might be a hopeful advancement in developing countries for treating cancers with the aid of toxic less natural based constituents....
BACKGROUND
Newly, chemo-preventive technique might be a hopeful advancement in developing countries for treating cancers with the aid of toxic less natural based constituents. Malignancy urges to augment effectual chemo-preventive agents that are look forward to suppress the tumours which may be stimulated by chewing and smoking of tobacco and over alcohol consumption related with the high prevalence of human oral cancer (OC) patients.
METHODS
In the present research, we examined to assess antioxidants, lipid peroxidation (LPO) and detoxification enzymes levels of anticancer activity of mangiferin on 0.5% 7.12-dimethylbenz[a]anthracene (DMBA) provoked hamster cheek pouch carcinoma (HCPC). OC on hamster buccal pouch (HBP) was incited by DMBA treatment for thrice per week for over 14 weeks.
RESULTS
100% well defined OC establishment with body weight (bw), tumour burden (TB), antioxidant, LPO and liver marker enzymes and also histological changes were observed on DMBA-challenged buccal pouch carcinoma (BPC) in hamsters. Orally treated mangiferin at an effective dosage of 50 mg/kg bw, to DMBA painted hamsters were significantly averted the body weight, succession of tumour, the biochemical as well as histopathological changes.
CONCLUSION
Findings of this work clearly suggest that the anti-carcinoma effect of mangiferin possesses the modulator effects on potent antioxidant, anti-LPO and detoxification agents to expel the metabolites of malignant cells, on DMBA-provoked BPC in hamsters.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Cricetinae; Humans; Mesocricetus; Mouth Neoplasms; Xanthones
PubMed: 33949808
DOI: 10.1002/vms3.500 -
Oncogene May 2021Cutaneous squamous cell carcinoma (cSCC) ranks second in the frequency of all skin cancers. The balance between keratinocyte proliferation and differentiation is...
Cutaneous squamous cell carcinoma (cSCC) ranks second in the frequency of all skin cancers. The balance between keratinocyte proliferation and differentiation is disrupted in the pathological development of cSCC. DLX3 is a homeobox transcription factor which plays pivotal roles in embryonic development and epidermal homeostasis. To investigate the impact of DLX3 expression on cSCC prognosis, we carried out clinicopathologic analysis of DLX3 expression which showed statistical correlation between tumors of higher pathologic grade and levels of DLX3 protein expression. Further, Kaplan-Meier survival curve analysis demonstrated that low DLX3 expression correlated with poor patient survival. To model the function of Dlx3 in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on mice genetically depleted of Dlx3 in skin epithelium (Dlx3cKO). Dlx3cKO mice developed significantly more tumors, with more rapid tumorigenesis compared to control mice. In Dlx3cKO mice treated only with DMBA, tumors developed after ~16 weeks suggesting that loss of Dlx3 has a tumor promoting effect. Whole transcriptome analysis of tumor and skin tissue from our mouse model revealed spontaneous activation of the EGFR-ERBB2 pathway in the absence of Dlx3. Together, our findings from human and mouse model system support a tumor suppressive function for DLX3 in skin and underscore the efficacy of therapeutic approaches that target EGFR-ERBB2 pathway.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Aged; Animals; Carcinogens; Carcinoma, Squamous Cell; Disease Models, Animal; ErbB Receptors; Female; Homeodomain Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Grading; Receptor, ErbB-2; Signal Transduction; Skin Neoplasms; Survival Rate; Tetradecanoylphorbol Acetate; Transcription Factors
PubMed: 33947961
DOI: 10.1038/s41388-021-01802-9 -
Journal of Mammary Gland Biology and... Jun 2021RNAscope is a quantitative in situ gene expression measurement technique that preserves the spatial aspect of intact tissue; thus, allowing for comparison of specific...
RNAscope is a quantitative in situ gene expression measurement technique that preserves the spatial aspect of intact tissue; thus, allowing for comparison of specific cell populations and morphologies. Reliable and accurate measurement of gene expression in tissue is dependent on preserving RNA integrity and the quantitative nature of RNAscope. The purpose of this study was to determine if the quantitative nature of RNAscope was retained following processing and carmine staining of mammary gland whole-mounts, which are commonly used to identify lesions, such as hyperplasia and ductal carcinoma in situ (DCIS). We were concerned that handling and procedures required to visualize microscopic disease lesions might compromise RNA integrity and the robustness of RNAscope. No effect on the quantitative abilities of RNAscope was detected when mammary gland whole-mounts were pre-screened for lesions of interest prior to RNAscope. This was determined in comparison to tissue that had been formalin-fixed and paraffin embedded (FFPE) immediately after collection. The ability to pre-screen whole-mounts allowed unpalpable diseased lesions to be identified without labor-intensive serial sectioning of tissue samples to find diseased tissue. This method is applicable to evaluate mammary gland whole-mounts during normal mammary gland development, function, and disease progression.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma, Intraductal, Noninfiltrating; Disease Models, Animal; Female; Gene Expression Profiling; Mammary Glands, Animal; Mammary Neoplasms, Experimental; RNA; Rats; Tissue Preservation
PubMed: 33866475
DOI: 10.1007/s10911-021-09484-5 -
Drug Research Jul 2021Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of attention in anti-cancer research over the past. In this study, phytochemicals from plants...
vHTS and 3D-QSAR for the Identification of Novel Phyto-inhibitors of Farnesyltransferase: Validation of Ascorbic Acid inhibition of Farnesyltransferase in an Animal Model of Breast Cancer.
Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of attention in anti-cancer research over the past. In this study, phytochemicals from plants were screened for their inhibitory potentials on the human farnesyltransferase. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the inhibition of farnesyltransferase was generated and the inhibition of farnesyltransferase by the hit, ascorbic acid was validated in an animal model of breast cancer. The lead compound, ascorbic acid makes extensive hydrogen bond interactions with key residues, lys-353, tyr-300, gly-290, leu-290 within the active site of farnesyltransferase. It downregulated the expression of FNTA mRNA in an animal model of breast cancer. The 3D-QSAR generated herein is robust, thoroughly validated, and should be employed in the pipelining of novel farnesyltransferase inhibitors. Ascorbic acid demonstrates its anticancer potentials through the inhibition of farnesyltransferase.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Anacardiaceae; Animals; Antineoplastic Agents, Phytogenic; Ascorbic Acid; Carcinogens; Curcuma; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Farnesyltranstransferase; Female; High-Throughput Screening Assays; Humans; Inhibitory Concentration 50; Mammary Neoplasms, Experimental; Molecular Docking Simulation; Quantitative Structure-Activity Relationship; Rats; Taraxacum
PubMed: 33862663
DOI: 10.1055/a-1422-1885 -
BioMed Research International 2021The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of extracts on skin carcinogenesis. Female Swiss albino mice were divided...
The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of extracts on skin carcinogenesis. Female Swiss albino mice were divided into five groups depending on the combination of skin cancer-inducing 7,12-dimethylbenz(a)anthracene (DMBA) and extract of treatments. Histology of the affected skin and measurement of proteasome activity were performed to demonstrate the effect of on mice. The identification of the molecules responsible for this inhibitory activity was carried out through the docking studies. The results showed that extracts inhibit the development of papilloma in mice. Therefore, the best chemopreventive action of was observed on mice in which extract treatment was performed before and after the induction of skin carcinogenesis. It was revealed that the ingestion of extracts delays the formation of skin papillomas in animals and simultaneously decreases the size and number of papillomas, which is also reflected on the skin histology of the mice treated. Structure-activity relationship information obtained from component of particularly tomentosin, inuviscolide, and isocosticacid demonstrated that distinct bonding modes in , , and subunits determine its selectivity and potent inhibition for subunit.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Caco-2 Cells; Chymotrypsin; Drug Evaluation, Preclinical; Female; Humans; Inula; Mice; Molecular Docking Simulation; Papilloma; Plant Extracts; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Skin Neoplasms; Toxicity Tests
PubMed: 33855081
DOI: 10.1155/2021/6687589