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Nature Communications Jul 2020Hormone receptor (HR) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers...
Hormone receptor (HR) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HRHER2 BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR BC.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Breast Neoplasms; Carcinogenesis; Disease Progression; Female; Humans; Immunotherapy; Interferon Type I; Mammary Neoplasms, Experimental; Medroxyprogesterone Acetate; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Niacinamide; Receptor, ErbB-2; Survival Analysis
PubMed: 32732875
DOI: 10.1038/s41467-020-17644-0 -
Journal of the Egyptian National Cancer... Sep 2022About 7 million people die from various types of cancer every year representing nearly 12.5% of deaths worldwide. This fact raises the demand to develop new, effective...
BACKGROUND
About 7 million people die from various types of cancer every year representing nearly 12.5% of deaths worldwide. This fact raises the demand to develop new, effective anticancer, onco-suppressive, and chemoprotective agents for the future fighting of cancers. Genistein exhibits pleiotropic functions in cancer, metabolism, and inflammation. It functions as an antineoplastic agent through its effect on the cell cycle, apoptotic processes, angiogenesis, invasion, and metastasis.
AIM OF THE STUDY
The current study aimed to study the genistein onco-suppressive effects during 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters' buccal pouch utilizing flow cytometry analysis (FMA), as a fast-diagnosing tool, in addition to the histopathology.
MATERIAL AND METHODS
The buccal mucosa of adult male Syrian hamsters was painted with paraffin oil only (group 1), DMBA mixed in mineral oil (group 2), or orally administrated genistein along with painting DMBA (group 2B). The buccal mucosa was utilized for flow cytometric analysis and histopathological examination.
RESULTS
Grossly, DMBA-induced carcinogenesis started at the 9th week. Progressive signs appeared in the following weeks reaching to large ulcerative oral masses and exophytic nodules at the 21st week. Histologically, invasive well-differentiated oral squamous cell carcinoma (OSCC) appeared in the underlying tissues from the 12th week, showing malignant criteria. Genistein had delayed clinicopathological change, which started 6 weeks later, than the DMBA-painted hamsters, as mild epithelial dysplastic changes. This became moderate during the last 6 weeks, without dysplastic changes. Flow cytometry revealed that DMBA led to considerable variation in DNA proliferation activity, aneuploid DNA pattern, in 47.22% of hamsters and significantly raised the S-phase fragment (SPF) values, which drastically reduced after genistein treatment.
CONCLUSION
Taken together, genistein could be employed as an onco-suppressive agent for carcinogenesis. Moreover, FMA could be used as an aiding fast tool for diagnosis of cancer.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Carcinoma, Squamous Cell; Cricetinae; Genistein; Head and Neck Neoplasms; Humans; Male; Mesocricetus; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck
PubMed: 36058937
DOI: 10.1186/s43046-022-00140-5 -
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 -
Breast Cancer Research : BCR Jul 2019Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain...
BACKGROUND
Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudin-low tumors nor those of human claudin-low breast tumors have been thoroughly explored.
METHODS
The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBA-induced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors.
RESULTS
Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently; however, none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation, and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors.
CONCLUSIONS
Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.
Topics: Animals; Biopsy; Claudins; DNA Copy Number Variations; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Mutation; Oncogenes; Transcriptome
PubMed: 31366361
DOI: 10.1186/s13058-019-1170-8 -
Journal of Environmental Pathology,... 2021The purpose of this study was to investigate the anti-inflammatory, antiproliferatiive, and proapoptotic molecular mechanisms of mangiferin (MGN) against mammary...
The purpose of this study was to investigate the anti-inflammatory, antiproliferatiive, and proapoptotic molecular mechanisms of mangiferin (MGN) against mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA). Mammary cancer in rats was induced by single-dose subcutaneous injection of 0.5 ml DMBA (80 mg/kg in sesame oil) in the mammary gland. Increased tumor incidence and volume and other tumorigenic properties were observed. Further, we observed in these rats reduced antioxidant enzyme activity and elevated thiobarbituric acid reactive substance (TBARS) levels in plasma and tissues. DMBA-induced rats shows enhanced expression of the inflammatory markers NF-κBp65, COX-2, and iNOS and proliferation of PCNA and Cyclin D1, and overexpression of the antiapoptotic marker Bcl-2. Mangiferin (100 mg/kg body weight), administered orally once per day, significantly enhanced (p < 0.05) antioxidant levels and reduced TBARS levels. Moreover, MGN inhibited NF-κBp65 nucleus transcriptional activation, thereby suppressing inflammation and cell proliferation, and it increased proapoptotic proteins. Apoptosis was confirmed by TUNEL assay. In summary, MGN suppressed DMBA-induced mammary carcinogenesis through enhanced antioxidant levels, NF-κB inhibition, and positive regulation of apoptotic signals.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Carcinogens; Cell Proliferation; Female; Mammary Glands, Animal; Mammary Neoplasms, Experimental; NF-kappa B; Rats, Sprague-Dawley; Xanthones; Rats
PubMed: 33822512
DOI: 10.1615/JEnvironPatholToxicolOncol.2021036057 -
Amino Acids Aug 2023Angiogenesis, invasion, and metastasis are the main events of cancer cells. JAK-1/STAT-3 is a key intracellular signaling transduction pathway, which controls the...
Angiogenesis, invasion, and metastasis are the main events of cancer cells. JAK-1/STAT-3 is a key intracellular signaling transduction pathway, which controls the growth, differentiation, apoptosis, invasion, and angiogenesis of various cancer cells. The present study explored the impact of allyl isothiocyanate (AITC) on the JAK-1/STAT-3 pathway in DMBA-induced rat mammary tumorigenesis. The mammary tumor was initiated through a single dose of 25 mg DMBA/rat by a subcutaneous injection administered near the mammary gland. We observed decreased body weight and increased the total number of tumors, tumor incidence, tumor volume, well-developed tumor, and histopathological abnormalities in DMBA-induced rats that were modulated after being treated with AITC. Staining of mammary tissues showed a high accumulation of collagen in DMBA-induced rats and it was normalized by the AITC treatment. Moreover, DMBA-induced mammary tissues showed up-regulated expressions of EGFR, pJAK-1, pSTAT-3, nuclear fraction of STAT-3, VEGF, VEGFR2, HIF-1α, MMP-2, and MMP-9 and the down-regulated expressions of cytosolic fraction of STAT-3 and TIMP-2. Oral administration of AITC on DMBA-induced rats inhibits angiogenesis and invasion by modifying these angiogenic and invasive markers. The finding of the present study was further confirmed by molecular docking analysis that shows a strong binding interaction between AITC with STAT-3 and cocrystal structure of STAT-3 glide energy of -18.123 and -72.246 (kcal/mole), respectively. Overall, the results suggested that AITC inhibits activation of the JAK-1/STAT-3 pathway, which subsequently prevents angiogenesis and invasion. It was recommended that AITC might develop a beneficial effect against breast cancer.
Topics: Rats; Animals; Molecular Docking Simulation; Signal Transduction; Neoplasms; ErbB Receptors; 9,10-Dimethyl-1,2-benzanthracene
PubMed: 37310534
DOI: 10.1007/s00726-023-03285-2 -
Archives of Dermatological Research May 2021Glypican-3 (GPC3) is considered as a cell surface heparan sulfate proteoglycan. It is overexpressed in skin cancer and promotes tumor progression and pathogenicity....
Glypican-3 (GPC3) is considered as a cell surface heparan sulfate proteoglycan. It is overexpressed in skin cancer and promotes tumor progression and pathogenicity. Therefore, we aimed to find out the therapeutic effects of immuno-suppressing GPC3 in skin cancer experimentally induced in mice as well as to underline molecular mechanisms especially inflammatory and apoptotic pathways. Skin cancer was experimentally induced in mice by repeated rubbing of mice skin with 7,12-dimethylbenz (a) anthracene. Mice were injected with anti-GPC3. Skin samples were isolated to investigate the gene and protein expression of GPC3, Wnt-1, NFκB, TNF-α, IGF-1, p38 MAPK and caspase-3 using PCR, Western blot and ELISA. Moreover, skin sections were stained with hematoxylin and eosin. Treating skin cancer mice with anti-GPC3 significantly blocked GPC3, which is accompanied by amelioration of skin cancer-induced increase in the numbers of tumors and scratching behavior. Moreover, anti-GPC3 attenuated skin cancer-induced increase in the expression of Wnt-1, NFκB, TNF-α, IGF-1, p38 MAPK and caspase-3. In parallel, anti-GPC3 reduced degeneration of melanocyte cells and reduced phagocytic cells epidermal hyperplasia and dysplasia in skin sections stained with hematoxylin and eosin stain. In conclusion, anti-GPC3 produced anti-tumor effects against skin cancer, which can be explained by reduction in both inflammatory and apoptotic pathways. Targeting GPC3 is a promising therapeutic approach for skin cancer.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Carcinogenesis; Carcinogens; Drug Screening Assays, Antitumor; Glypicans; Humans; Mice; Neoplasms, Experimental; Skin; Skin Neoplasms
PubMed: 32638071
DOI: 10.1007/s00403-020-02102-0 -
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 -
The Journal of Investigative Dermatology Jun 2022Type 2 inflammation‒related cytokine IL-13 plays a protective role in experimental papilloma induction in mice. To understand the mechanisms by which IL-13 contributes...
Type 2 inflammation‒related cytokine IL-13 plays a protective role in experimental papilloma induction in mice. To understand the mechanisms by which IL-13 contributes to papilloma formation, we utilized Il13rα1-knockout (KO) mice in a widely used 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoyl phorbol-13-acetate two-stage skin carcinogenesis protocol that mimics the development of squamous cell carcinoma. KO mice developed more papillomas and significantly faster than wild-type mice. Papilloma development reduced regulatory T cells in wild-type mice but substantially less in KO mice. In line with this, IL-2 and IL-10 levels decreased in wild-type mice but not in KO mice. Furthermore, systemic IL-5 and TSLP levels were elevated, whereas IL-22 was decreased during papilloma formation in the skin of KO mice. Polymorphonuclear myeloid‒derived suppressor cells were decreased in the KO mice at the early phase of papilloma induction. We show that IL-13Rα1 protects from papilloma development in chemically induced skin carcinogenesis, and our results provide further insights into the protective role of functional IL-4 and IL-13 signaling through type II IL-4 receptor in tumor development.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Carcinogens; Interleukin-13; Interleukin-13 Receptor alpha1 Subunit; Mice; Mice, Knockout; Papilloma; Skin Neoplasms; T-Lymphocytes, Regulatory; Tetradecanoylphorbol Acetate
PubMed: 34808240
DOI: 10.1016/j.jid.2021.11.013 -
Scientific Reports May 2023Breast cancer is the second leading cause of cancer death among women. The present study is an effort to reveal the antiproliferative and antioxidant actions of mango...
Breast cancer is the second leading cause of cancer death among women. The present study is an effort to reveal the antiproliferative and antioxidant actions of mango seed kernel extract (KE), peel extract (PE), and their combination (KEPE) on mammary tumors induced by 7,12 dimethylbenz[a]anthracene (DMBA). Seven groups of adult female Sprague-Dawley rats were prepared, including C: (control), DMBA: (rats were administered with DMBA), (DMBA-KE), (DMBA-PE), and (DMBA-KEPE): rats were administered with DMBA and then treated with KE, PE, and (both KE and PE), respectively, (KE) and (PE): rats were administered with KE and PE, separately. The study focused on the assessment of markers of endocrine derangement [serum 17-β estradiol (E2)], apoptosis [caspase-3 and deoxyribonucleic acid fragmentation (DNAF)], and oxidative stress [lipid peroxidation and antioxidants (glutathione, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, and superoxide dismutase)]. Histopathological examination and immunohistochemical expression of caspase-3 and estrogen receptor-α (ER-α) in mammary gland tissues (MGTs) were determined, as well as the characterization of mango extracts. The results showed that DMBA administration induced mammary tumors by increasing cell proliferation and evading apoptosis. In addition, DMBA administration caused oxidative stress by the production of reactive oxygen species, which increased lipid peroxidation and decreased cellular antioxidants, allowing cancer to progress. In contrast, treatment with DMBA-KE, DMBA-PE, or DMBA-KEPE diminished mammary tumors induced by DMBA, where they reduced oxidative stress via increased antioxidant parameters including reduced glutathione, superoxide dismutase, total glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Also, different treatments decreased proliferation through the reduction of E2, and ER-α expression levels. However, these treatments increased the apoptosis of unwanted cells as they increased caspase-3 activity and DNAF. All these changes led to the prevention of breast injuries and the reduction of mammary tumors. This demonstrates that the contents of mango extracts, especially phenolics and flavonoids, have an important role in mammary tumor treatment through their potential antioxidant, antiproliferative, proapoptotic, and anti-estrogenic effects. KE and PE administration for 4 weeks had no adverse effects. Conclusion: Each of KE, PE, and KEPE has a therapeutic effect against DMBA-induced mammary tumors via induction of apoptosis and reduction of each of the OS, proliferation, and estrogenic effects. So, they can play an important role in the pharmacological tole.
Topics: Rats; Female; Animals; Antioxidants; Rats, Sprague-Dawley; Mangifera; Caspase 3; 9,10-Dimethyl-1,2-benzanthracene; Mammary Neoplasms, Experimental; Glutathione; Superoxide Dismutase; Carcinogenesis; Oxidoreductases
PubMed: 37169856
DOI: 10.1038/s41598-023-34626-6