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Gut Microbes 2023The microbiota plays critical roles in regulating the function and health of the intestine and extraintestinal organs. A fundamental question is whether an...
The microbiota plays critical roles in regulating the function and health of the intestine and extraintestinal organs. A fundamental question is whether an intestinal-microbiome-breast axis exists during the development of breast cancer. If so, what are the roles of host factors? Vitamin D receptor (VDR) involves host factors and the human microbiome. Vdr gene variation shapes the human microbiome, and VDR deficiency leads to dysbiosis. We hypothesized that intestinal VDR protects hosts against tumorigenesis in the breast. We examined a 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer model in intestinal epithelial VDR knockout (VDR) mice with dysbiosis. We reported that VDR mice with dysbiosis are more susceptible to breast cancer induced by DMBA. Intestinal and breast microbiota analysis showed that VDR deficiency leads to a bacterial profile shift from normal to susceptible to carcinogenesis. We found enhanced bacterial staining within breast tumors. At the molecular and cellular levels, we identified the mechanisms by which intestinal epithelial VDR deficiency led to increased gut permeability, disrupted tight junctions, microbial translocation, and enhanced inflammation, thus increasing tumor size and number in the breast. Furthermore, treatment with the beneficial bacterial metabolite butyrate or the probiotic Lactobacillus plantarum reduced breast tumors, enhanced tight junctions, inhibited inflammation, increased butyryl-CoA transferase, and decreased levels of breast Streptococcus bacteria in VDR mice. The gut microbiome contributes to the pathogenesis of diseases not only in the intestine but also in the breast. Our study provides insights into the mechanism by which intestinal VDR dysfunction and gut dysbiosis lead to a high risk of extraintestinal tumorigenesis. Gut-tumor-microbiome interactions represent a new target in the prevention and treatment of breast cancer.
Topics: Humans; Mice; Animals; Female; Receptors, Calcitriol; Breast Neoplasms; Dysbiosis; Gastrointestinal Microbiome; Inflammation; Carcinogenesis; Cell Transformation, Neoplastic; Gastrointestinal Diseases; Bacteria; Intestinal Mucosa
PubMed: 37074210
DOI: 10.1080/19490976.2023.2202593 -
EMBO Reports Jun 2022Interleukin-38 (IL-38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that...
Interleukin-38 (IL-38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that expression of IL-38, which exhibits high expression in the skin, is downregulated in human cutaneous squamous cell carcinoma and 7,12-dimethylbenzanthracene/12-O-tetradecanoyl phorbol-13-acetate-induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice displayed suppressed skin tumor formation and malignant progression. Keratinocyte-specific deletion of IL-38 was associated with reduced expression of inflammatory cytokines, leading to reduced myeloid cell infiltration into the local tumor microenvironment. IL-38 is dispensable for epidermal mutagenesis, but IL-38 keratinocyte-specific deletion reduces proliferative gene expression along with epidermal cell proliferation and hyperplasia. Mechanistically, we first demonstrated that IL-38 activates the c-Jun N-terminal kinase (JNK)/activator protein 1 signal transduction pathway to promote the expression of cancer-related inflammatory cytokines and proliferation and migration of tumor cells in an IL-1 receptor-related protein 2 (IL-1Rrp2)-dependent manner. Our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2/JNK and suggest IL-38/IL-1Rrp2 as a preventive and potential therapeutic target in skin cancer.
Topics: Animals; Carcinogenesis; Carcinoma, Squamous Cell; Cytokines; Hyperplasia; Interleukin-1; Interleukins; Mice; Receptors, Interleukin-1; Skin; Skin Neoplasms; Tumor Microenvironment
PubMed: 35578812
DOI: 10.15252/embr.202153791 -
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 -
Scientific Reports Jan 2022Mammary carcinoma, breast cancer, is the most commonly diagnosed cancer type among women. Therefore, potential new technologies for the diagnosis and treatment of the...
Mammary carcinoma, breast cancer, is the most commonly diagnosed cancer type among women. Therefore, potential new technologies for the diagnosis and treatment of the disease are being investigated. One promising technique is microwave applications designed to exploit the inherent dielectric property discrepancy between the malignant and normal tissues. In theory, the anomalies can be characterized by simply measuring the dielectric properties. However, the current measurement technique is error-prone and a single measurement is not accurate enough to detect anomalies with high confidence. This work proposes to classify the rat mammary carcinoma, based on collected large-scale in vivo S[Formula: see text] measurements and corresponding tissue dielectric properties with a circular diffraction antenna. The tissues were classified with high accuracy in a reproducible way by leveraging a learning-based linear classifier. Moreover, the most discriminative S[Formula: see text] measurement was identified, and to our surprise, using the discriminative measurement along with a linear classifier an 86.92% accuracy was achieved. These findings suggest that a narrow band microwave circuitry can support the antenna enabling a low-cost automated microwave diagnostic system.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma; Electric Conductivity; Electrodiagnosis; Female; Machine Learning; Mammary Neoplasms, Experimental; Microwaves; Predictive Value of Tests; Rats, Sprague-Dawley; Reproducibility of Results; Rats
PubMed: 35013545
DOI: 10.1038/s41598-021-03884-7 -
Scientific Reports Mar 2022Imbalanced glucose tolerance and insulin resistance remain important as high cancer risk factors. Metformin administration to diabetic patients may be associated with a...
Imbalanced glucose tolerance and insulin resistance remain important as high cancer risk factors. Metformin administration to diabetic patients may be associated with a reduced risk of malignancy. The combined effects of the hormone melatonin and metformin in oncology practice have shown positive results. The relevance of our study is to find out the role of specific biomarkers of lysosome destruction and oxidative stress data in carcinogenesis models. The present study was designed to investigate the comparative synergic effect of peroral antidiabetic metformin (MF) and pineal hormone melatonin (MEL) administered alone and in combination in two different rat's models of mammary tumour proliferation in vivo (N-methyl-N-nitrosourea, NMU or 7,12-dimethylbenz[a]anthracene, DMBA). We have studied the processes of lysosomal destruction (alanyl aminopeptidase AAP, leucyl aminopeptidase LAP, acid phosphatase AcP, β-N-acetylglucosaminidase NAG, β-galactosidase β-GD and β-glucuronidase β-GR) caused by evaluated oxidative stress in three types of tissues (liver, heart, and spleen) in female Sprague-Dawley rats fed a high-fat diet (10% of total fat: 2.5% from lard and 7.5% from palm olein). Our results revealed an increase in the activity of the studied lysosomal enzymes and their expression in a tissue-specific manner depending on the type of chemical agent (NMU or DMBA). MANOVA tests in our study confirmed the influence of the three main factors, type of tissue, chemical impact, and chemopreventive agents, and the combinations of these factors on the lysosomal activity induced during the process of cancerogenesis. The development and induction of the carcinogenesis process in the different rat models with the high-fat diet impact were also accompanied by initiation of free-radical oxidation processes, which we studied at the initial (estimated by the level of diene conjugates) and final (TBARS products) stages of this process. The combined effects of MEL and MF for the two models of carcinogenesis at high-fat diet impact for AAP, LAP, and AcP showed a significant synergistic effect when they impact together when compared with the effects of one substance alone (either MEL or MF) in the breast cancer model experiments. Synergistic effects of limiting destructive processes of lysosomal functioning β-GD enzyme activity we obtained in experiments with MEL and MF chemoprevention for both models of carcinogenesis for three tissues. The statistical SS test allowed us to draw the following conclusions on the role of each lysosomal parameter analyzed as an integral model: NAG > AcP > β-GD > β-GR > AAP > LAP.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Autophagy; Carcinogenesis; Diet, High-Fat; Female; Humans; Lysosomes; Mammary Neoplasms, Experimental; Melatonin; Metformin; Oxidative Stress; Rats; Rats, Sprague-Dawley
PubMed: 35322049
DOI: 10.1038/s41598-022-08778-w -
Breast Cancer Research : BCR Mar 2021Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and...
BACKGROUND
Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. TGFB1 also plays roles in tumour development and progression, and its increased expression is associated with an increased breast cancer risk. Macrophages are key target cells for TGFB1 action, also playing crucial roles in tumourigenesis. However, the precise role of TGFB-regulated macrophages in the mammary gland is unclear. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice.
METHODS
A transgenic mouse model was generated, wherein a dominant negative TGFB receptor is activated in macrophages, in turn attenuating the TGFB signalling pathway specifically in the macrophage population. The mammary glands were assessed for morphological changes through wholemount and H&E analysis, and the abundance and phenotype of macrophages were analysed through immunohistochemistry. Another cohort of mice received carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), and tumour development was monitored weekly. Human non-neoplastic breast tissue was also immunohistochemically assessed for latent TGFB1 and macrophage marker CD68.
RESULTS
Attenuation of TGFB signalling resulted in an increase in the percentage of alveolar epithelium in the mammary gland at dioestrus and an increase in macrophage abundance. The phenotype of macrophages was also altered, with inflammatory macrophage markers iNOS and CCR7 increased by 110% and 40%, respectively. A significant decrease in DMBA-induced mammary tumour incidence and prolonged tumour-free survival in mice with attenuated TGFB signalling were observed. In human non-neoplastic breast tissue, there was a significant inverse relationship between latent TGFB1 protein and CD68-positive macrophages.
CONCLUSIONS
TGFB acts on macrophage populations in the mammary gland to reduce their abundance and dampen the inflammatory phenotype. TGFB signalling in macrophages increases mammary cancer susceptibility potentially through suppression of immune surveillance activities of macrophages.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Disease Susceptibility; Disease-Free Survival; Epithelial Cells; Estrous Cycle; Female; Humans; Inflammation; Macrophages; Mammary Glands, Animal; Mammary Glands, Human; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta1
PubMed: 33761981
DOI: 10.1186/s13058-021-01417-8 -
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 -
Asian Pacific Journal of Cancer... Aug 2022Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer, showing poor prognosis and high mortality. Meanwhile, cancer metabolism is an essential...
BACKGROUND AND AIM OF THE STUDY
Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer, showing poor prognosis and high mortality. Meanwhile, cancer metabolism is an essential contributor to its progression and response to treatment. This research aims to investigating the effect of a glucose-rich and glucose-free diet on the progress of oral squamous cell carcinoma induced in hamsters.
MATERIALS AND METHODS
forty Syrian Hamsters were incubated in two groups. The first one consisted of twenty hamsters, in which the carcinogenic material (DMBA) was applied in the buccal pouch of the hamster three days per week with a glucose-rich diet). The second one was composed of twenty hamsters, in which the carcinogenic material (DMBA) was applied in the buccal pouch three days per week with a glucose-free diet). Hamsters in both groups were sacrificed in groups of five hamsters at a time and at intervals (two weeks, six weeks, ten weeks, and Fourteen weeks). A histological study was performed after conventional staining with hematoxylin and eosin was done.
RESULTS
After two weeks of the experiment hyperplasia, mild dysplasia, and moderate dysplasia were recorded in hamster buccal pockets with a glucose-rich diet, and after six weeks moderate dysplasia, severe dysplasia, and carcinomas in situ were recorded, after ten weeks severe dysplasia, carcinomas in situ, and OSCC, after fourteen weeks OSCC were recorded. While with a glucose-free diet Hyperkeratosis, hyperplasia, and mild dysplasia were observed after a two-week the experiment, after six weeks, mild dysplasia, moderate dysplasia, and severe dysplasia were recorded, after ten weeks, moderate dysplasia, severe dysplasia, and carcinoma in situ, after fourteen weeks Severe dysplasia, carcinoma in situ, and OSCC were reported.
CONCLUSION
our results showed that a glucose-free diet slightly prevents oral squamous cell carcinoma, It may be a supportive treatment in addition to conventional cancer treatment.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Carcinogens; Carcinoma in Situ; Carcinoma, Squamous Cell; Cricetinae; Glucose; Head and Neck Neoplasms; Humans; Hyperplasia; Mesocricetus; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck
PubMed: 36037144
DOI: 10.31557/APJCP.2022.23.8.2857 -
Marine Drugs Aug 2023The carotenoids mixture (MC) isolated from the starfish contains more than 50% astaxanthin, 4-6% each zeaxanthine and lutein, and less pharmacologically active...
The carotenoids mixture (MC) isolated from the starfish contains more than 50% astaxanthin, 4-6% each zeaxanthine and lutein, and less pharmacologically active components such as free fatty acids and their glycerides. Astaxanthin, the major component of MC, belongs to the xanthophyll class of carotenoids, and is well known for its antioxidant properties. In this work, in vitro and in vivo studies on the biological activity of MC were carried out. The complex was shown to exhibit anti-inflammatory, anti-allergic and cancer-preventive activity, without any toxicity at a dose of 500 mg/kg. MC effectively improves the clinical picture of the disease progressing, as well as normalizing the cytokine profile and the antioxidant defense system in the in vivo animal models of inflammatory diseases, namely: skin carcinogenesis, allergic contact dermatitis (ACD) and systemic inflammation (SI). In the skin carcinogenesis induced by 7,12-dimethylbenzanthracene, the incidence of papillomas was decreased 1.5 times; 1% MC ointment form in allergic contact dermatitis showed an 80% reduced severity of pathomorphological skin manifestations. Obtained results show that MC from starfish is an effective remedy for the treatment and prevention of inflammatory processes.
Topics: Animals; Starfish; Carotenoids; Antioxidants; Lutein; Anti-Allergic Agents; Carcinogenesis; Dermatitis, Allergic Contact
PubMed: 37755083
DOI: 10.3390/md21090470 -
Carcinogenesis Jul 2020Previous studies demonstrate that the heavy metal cadmium and the metalloid arsenite activate estrogen receptor-alpha in breast cancer cells by forming a high-affinity...
Previous studies demonstrate that the heavy metal cadmium and the metalloid arsenite activate estrogen receptor-alpha in breast cancer cells by forming a high-affinity complex with the ligand-binding domain of the receptor and that environmentally relevant doses of cadmium have estrogen-like activity in vivo. The present study showed that in estrogen-receptor positive cells, arsenite and cadmium increased the global expression of estrogen-responsive genes and that an environmentally relevant dose of arsenite also had estrogen-like activity in vivo. Similar to estrogens, exposure of ovariectomized animals to arsenite induced the expression of the progesterone receptor, GREB1, and c-fos in the mammary gland and the expression of complement C3, c-fos, and cyclin D1 in the uterus and the increase was blocked by the antiestrogen ICI-182,780. When virgin female animals were fed a diet, that mimics exposure to either arsenite or cadmium, and challenged with the chemical carcinogen dimethylbenzanthracene, there was an increase in the incidence of mammary tumors and a decrease in the time to tumor onset, but no difference in the total number of tumors, tumor multiplicity, or total tumor volume. Together with published results, these data showed that environmentally relevant amounts of arsenite and cadmium had estrogen-like activity in vivo and promoted mammary tumorigenesis.
Topics: Animals; Arsenites; Benz(a)Anthracenes; Cadmium; Carcinogens; Cyclin D1; Estrogen Receptor alpha; Estrogens; Female; Humans; MCF-7 Cells; Mammary Glands, Human; Mammary Neoplasms, Animal; Neoplasm Proteins; Proto-Oncogene Proteins c-fos; Rats; Receptors, Progesterone
PubMed: 31646340
DOI: 10.1093/carcin/bgz176