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Spectrochimica Acta. Part A, Molecular... Sep 2024The development of tools that can provide a holistic picture of the evolution of the tumor microenvironment in response to intermittent fasting on the prevention of...
The development of tools that can provide a holistic picture of the evolution of the tumor microenvironment in response to intermittent fasting on the prevention of breast cancer is highly desirable. Here, we show, for the first time, the use of label-free Raman spectroscopy to reveal biomolecular alterations induced by intermittent fasting in the tumor microenvironment of breast cancer using a dimethyl-benzanthracene induced rat model. To quantify biomolecular alterations in the tumor microenvironment, chemometric analysis of Raman spectra obtained from untreated and treated tumors was performed using multivariate curve resolution-alternative least squares and support vector machines. Raman measurements revealed remarkable and robust differences in lipid, protein, and glycogen content prior to morphological manifestations in a dynamically changing tumor microenvironment, consistent with the proteomic changes observed by quantitative mass spectrometry. Taken together with its non-invasive nature, this research provides prospective evidence for the clinical translation of Raman spectroscopy to identify biomolecular variations in the microenvironment induced by intermittent fasting for the prevention of breast cancer, providing new perspectives on the specific molecular effects in the tumorigenesis of breast cancer.
Topics: Spectrum Analysis, Raman; Animals; Female; Fasting; Tumor Microenvironment; Breast Neoplasms; Rats; Disease Models, Animal; 9,10-Dimethyl-1,2-benzanthracene; Mammary Neoplasms, Experimental; Rats, Sprague-Dawley; Intermittent Fasting
PubMed: 38704999
DOI: 10.1016/j.saa.2024.124387 -
Anticancer Research May 2024Breast cancer is a leading cause of cancer-related deaths among women. Down-regulation of the tumor suppressor gene Cyld in breast cancer has been linked to a poor...
BACKGROUND/AIM
Breast cancer is a leading cause of cancer-related deaths among women. Down-regulation of the tumor suppressor gene Cyld in breast cancer has been linked to a poor prognosis. This study investigated the role of Cyld in breast cancer using conditional mutant mouse models carrying a Cyld mutation, which inactivates the deubiquitinating activity of its protein product CYLD in mammary epithelial cells.
MATERIALS AND METHODS
We examined the potential of CYLD inactivation to induce mammary tumors spontaneously or modify the susceptibility of mice to mammary tumorigenesis by DMBA treatment or ErbB2 over-expression.
RESULTS
CYLD inactivation significantly increased susceptibility to breast cancer induced by either DMBA treatment or ErbB2 over-expression. Moreover, while CYLD inactivation alone did not lead to spontaneous mammary tumorigenesis, it did contribute to the formation of multifocal hyperplastic lesions in virgin mice of predominantly FVB/NJ background.
CONCLUSION
Our study demonstrates the tumor enhancing potential of CYLD inactivation in mammary tumorigenesis in vivo and establishes novel relevant mouse models that can be exploited for developing prognostic and therapeutic protocols.
Topics: Animals; Female; Mice; 9,10-Dimethyl-1,2-benzanthracene; Breast Neoplasms; Cell Transformation, Neoplastic; Deubiquitinating Enzyme CYLD; Mammary Neoplasms, Experimental; Mutation; Receptor, ErbB-2; Tumor Suppressor Proteins
PubMed: 38677721
DOI: 10.21873/anticanres.16990 -
Toxicology and Applied Pharmacology May 2024Obesity impairs oocyte quality, fertility, pregnancy maintenance, and is associated with offspring birth defects. The model ovotoxicant, 7,12-dimethylbenz[a]anthracene...
Exposure to 7,12-dimethylbenz[a]anthracene impacts ovarian DNA damage sensing and repair proteins differently in lean and obese female mice and weight loss may mitigate obesity-induced ovarian dysfunction.
Obesity impairs oocyte quality, fertility, pregnancy maintenance, and is associated with offspring birth defects. The model ovotoxicant, 7,12-dimethylbenz[a]anthracene (DMBA), causes ovarian DNA damage and follicle loss. Both DMBA-induced chemical biotransformation and the DNA damage response are partially attenuated in obese relative to lean female mice but whether weight loss could improve the DNA damage response to DMBA exposure has not been explored. Thus, at six weeks of age, C57BL/6 J female mice were divided in three groups: 1) Lean (L; n = 20) fed a chow diet for 12 weeks, 2) obese (O; n = 20) fed a high fat high sugar (HFHS) diet for 12 weeks and, 3) slim-down (S; n = 20). The S group was fed with HFHS diet for 7 weeks until attaining a higher body relative to L mice on week 7.5 and switched to a chow diet for 5 weeks to achieve weight loss. Mice then received either corn oil (CT) or DMBA (D; 1 mg/kg) for 7 d via intraperitoneal injection (n = 10/treatment). Obesity increased (P < 0.05) kidney and spleen weight, and DMBA decreased uterine weight (P < 0.05). Ovarian weight was reduced (P < 0.05) in S mice, but DMBA exposure increased ovary weight in the S mice. LC-MS/MS identified 18, 64, and 7 ovarian proteins as altered (P < 0.05) by DMBA in the L, S and O groups, respectively. In S and O mice, 24 and 8 proteins differed, respectively, from L mice. These findings support weight loss as a strategy to modulate the ovarian genotoxicant response.
Topics: Animals; Female; 9,10-Dimethyl-1,2-benzanthracene; Obesity; DNA Damage; Mice, Inbred C57BL; Weight Loss; Ovary; Mice; DNA Repair; Ovarian Diseases; Diet, High-Fat
PubMed: 38626870
DOI: 10.1016/j.taap.2024.116930 -
The American Journal of Pathology Jul 2024A remote carcinogen exposure can predispose to breast cancer onset decades later, suggesting that carcinogen-induced mutations generate long-lived premalignant clones....
A remote carcinogen exposure can predispose to breast cancer onset decades later, suggesting that carcinogen-induced mutations generate long-lived premalignant clones. How subsequent events influence the progression of specific premalignant clones remains poorly understood. Herein, multistage mouse models of mammary carcinogenesis were generated by combining chemical carcinogen exposure [using 7,12-dimethylbenzanthracene (DMBA)] with transgenes that enable inducible expression of one of two clinically relevant mammary oncogenes: c-MYC (MYC) or PIK3CA (PIK). In prior work, DMBA exposure generated mammary clones bearing signature Hras mutations, which only progressed to mammary cancer after inducible Wnt1 oncogene expression. Here, after an identical DMBA exposure, MYC versus PIK drove cancer progression from mammary clones bearing mutations in distinct Ras family paralogs. For example, MYC drove cancer progression from either Kras- or Nras-mutant clones, whereas PIK transformed Kras-mutant clones only. These Ras mutation patterns were maintained whether oncogenic transgenes were induced within days of DMBA exposure or months later. Completing a full-term pregnancy (parity) failed to protect against either MYC- or PIK-driven tumor progression. Instead, a postpartum increase in mammary tumor predisposition was observed in the context of PIK-driven progression. However, parity decreased the overall prevalence of tumors bearing Kras, and the magnitude of this decrease depended on both the number and timing of pregnancies. These multistage models may be useful for elucidating biological features of premalignant mammary neoplasia.
Topics: Animals; Female; Mice; Mammary Neoplasms, Experimental; Disease Progression; Oncogenes; Precancerous Conditions; 9,10-Dimethyl-1,2-benzanthracene; Mice, Transgenic; Disease Models, Animal; Mutation; Class I Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-myc
PubMed: 38537934
DOI: 10.1016/j.ajpath.2024.02.018 -
Journal of Complementary & Integrative... Jun 2024L. seeds; rich in zinc and lignans are endowed with antioxidant and immunomodulatory properties which attract research on their anticancer potential. Although many...
OBJECTIVES
L. seeds; rich in zinc and lignans are endowed with antioxidant and immunomodulatory properties which attract research on their anticancer potential. Although many studies have reported the antitumor potential of and its phytoconstituents, much is yet to be known about its effects. To fill this gap, the effects of dietary supplementation with seeds of in 7,12-dimethylbenz(a)anthracene-exposed rats was assessed.
METHODS
42 rats aged 30-35 days were randomized into six groups (n=6) as follows: the normal (NOR) and negative (DMBA) control groups were fed with standard diet; the positive control group (DMBA + Zinc) was fed with standard diet supplemented with commercial zinc (0.01 %); the test groups were fed with standard diet supplemented with seeds in different proportions (6.25 , 12.5 and 25 %). Breast cancer was induced by a single administration of DMBA (50 mg/kg BW, ) diluted in corn oil. The experiment lasted 20 weeks and afterward, tumor incidence; tumor burden, tumor volume, tumor micro-architecture and some biochemical parameters were evaluated.
RESULTS
As salient result, 100 % of rats in the DMBA group developed tumors, while rats feed with rat chow supplemented with seeds (25 %) had a reduced incidence of tumors (33.3 %) and tumor volume (2.71 cm in sesame 25 % vs. 4.69 cm in the DMBA group, p˂0.01). The seeds (25 %) also slowed DMBA-induced neoplasm expansion in mammary ducts as compared to rats of DMBA group.
CONCLUSIONS
In summary, supplementation with seeds slowed breast tumorigenesis via its antioxidant capacity.
Topics: Animals; Sesamum; Seeds; Female; Dietary Supplements; Rats; 9,10-Dimethyl-1,2-benzanthracene; Plant Extracts; Mammary Neoplasms, Experimental; Tumor Burden; Antioxidants; Breast Neoplasms
PubMed: 38515384
DOI: 10.1515/jcim-2023-0266 -
Molecular Oncology Mar 2024Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1...
Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via the type I interferon pathway in PD-L1-expressing head and neck cancer.
Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1 ligand 1 (PD-L1; also known as CD274 molecule)-expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE-048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou oral cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in the TME, including vascular normalization. Furthermore, the antitumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). The ICB-induced antitumorigenicity and TME normalization were alleviated by blocking the type I interferon pathway. In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the type I interferon pathway is indispensable in realizing the effects of ICBs. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against PD-L1-expressing HNSCC in the KEYNOTE-048 trial.
PubMed: 38511232
DOI: 10.1002/1878-0261.13633 -
NPJ Systems Biology and Applications Mar 2024Skin cancer and other skin-related inflammatory pathologies are rising due to heightened exposure to environmental pollutants and carcinogens. In this context, natural...
Skin cancer and other skin-related inflammatory pathologies are rising due to heightened exposure to environmental pollutants and carcinogens. In this context, natural products and repurposed compounds hold promise as novel therapeutic and preventive agents. Strengthening the skin's antioxidant defense mechanisms is pivotal in neutralizing reactive oxygen species (ROS) and mitigating oxidative stress. Sunset Yellow (SY) exhibits immunomodulatory characteristics, evidenced by its capacity to partially inhibit the secretion of proinflammatory cytokines, regulate immune cell populations, and modulate the activation of lymphocytes. This study aimed to investigate the antioxidant and anti-genotoxic properties of SY using in-silico, in vitro, and physiochemical test systems, and to further explore its potential role in 7,12-dimethylbenz(a) anthracene (DMBA)/ 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis. In vitro experiments showed that pre-treatment of SY significantly enhanced the cell viability of HaCaT cells when exposed to tertiary-Butyl Hydrogen Peroxide (tBHP). This increase was accompanied by reduced ROS levels, restoration of mitochondrial membrane potential, and notable reduction in DNA damage in (SY + tBHP) treated cells. Mechanistic investigations using DPPH chemical antioxidant activity test and potentiometric titrations confirmed SY's antioxidant properties, with a standard reduction potential ( ) of 0.211 V. Remarkably, evaluating the effect of topical application of SY in DMBA/TPA-induced two-step skin carcinogenesis model revealed dose-dependent decreases in tumor latency, incidence, yield, and burden over 21-weeks. Furthermore, computational analysis and experimental validations identified GSK3β, KEAP1 and EGFR as putative molecular targets of SY. Collectively, our findings reveal that SY enhances cellular antioxidant defenses, exhibits anti-genotoxic effects, and functions as a promising chemopreventive agent.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; Antioxidants; Reactive Oxygen Species; NF-E2-Related Factor 2; 9,10-Dimethyl-1,2-benzanthracene; Skin Neoplasms; Tetradecanoylphorbol Acetate; Oxidative Stress; Chemoprevention; Carcinogenesis; Azo Compounds
PubMed: 38431714
DOI: 10.1038/s41540-024-00349-1 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Jan 2024This paper aims to explore the inhibitory effect of Yueju Pills on breast cancer and decipher the underlying mechanism. A total of 92 SPF-grade SD female rats were...
This paper aims to explore the inhibitory effect of Yueju Pills on breast cancer and decipher the underlying mechanism. A total of 92 SPF-grade SD female rats were involved in this study, and 14 of them were randomly selected into control group. The remaining 78 rats were administrated with 7,12-dimethylbenzanthracene(DMBA) by gavage to establish the breast cancer model. The modeled rats were randomized into model, tamoxifen(1.9 mg·kg~(-1)·d~(-1)), and low-and high-dose(17, 34 g·kg~(-1)·d~(-1)) Yueju Pills groups. The mental state, food intake, and activities of the rats were observed daily, and the body weight was measured on alternate days. After 12 weeks of administration, the rats were sacrificed and the tumor weight was measured. The serum estrogen and progeste-rone levels were determined by enzyme-linked immunosorbent assay. The histopathological changes of the breast and tumor were observed by hematoxylin-eosin staining. Western blot was employed to measure the protein levels of glucose transporter 1(GLUT1), lactate dehydrogenase A(LDHA), phosphofructokinase muscle(PFKM), pyruvate kinase isozyme type M2(PKM2), hexokinase 2(HK2), nuclear factor-kappaB(NF-κB), and phosphorylated NF-κB. The intestinal microbiome was examined by 16S rRNA high-throughput sequencing. The results showed that compared with the model group, high and low-dose Yueju Pills showed the tumor inhibition rate of 15.8% and 64.5%, respectively, and the low dose group had stronger inhibitory effect. Compared with the control group, the model group presented elevated the levels of estrogen and progesterone in serum. The administration of Yueju Pills lowered such ele-vation, and the low-dose group showed stronger lowering effect(P<0.05). Compared with the model group, Yueju Pills reduced the glands with increased breast tissue, the degree of breast duct expansion, the number and area of acinar cavity, the secretions, and the layers of mammary epithelial cells. Furthermore, Yueju Pills down-regulated the expression of GLUT1, LDHA, PFKM, PKM2, HK2, and NF-κB(P<0.05) and altered the diversity, composition, structure, and abundance of intestinal flora. The results showed that Yueju Pills could inhibit breast cancer by regulating the secretion of estrogen and progesterone, glycolysis, inflammatory cytokines, and intestinal flora.
Topics: Rats; Female; Animals; 9,10-Dimethyl-1,2-benzanthracene; NF-kappa B; Progesterone; Glucose Transporter Type 1; RNA, Ribosomal, 16S; Neoplasms; Estrogens
PubMed: 38403319
DOI: 10.19540/j.cnki.cjcmm.20230919.401 -
Pharmaceutics Jan 2024The study aimed to evaluate the antitumor and toxicogenetic effects of liposomal nanoformulations containing citrinin in animal breast carcinoma induced by...
The study aimed to evaluate the antitumor and toxicogenetic effects of liposomal nanoformulations containing citrinin in animal breast carcinoma induced by 7,12-dimethylbenzanthracene (DMBA). virgin females were divided into six groups treated with (1) olive oil (10 mL/kg); (2) 7,12-DMBA (6 mg/kg); (3) citrinin, CIT (2 mg/kg), (4) cyclophosphamide, CPA (25 mg/kg), (5) liposomal citrinin, LP-CIT (2 μg/kg), and (6) LP-CIT (6 µg/kg). Metabolic, behavioral, hematological, biochemical, histopathological, and toxicogenetic tests were performed. DMBA and cyclophosphamide induced behavioral changes, not observed for free and liposomal citrinin. No hematological or biochemical changes were observed for LP-CIT. However, free citrinin reduced monocytes and caused hepatotoxicity. During treatment, significant differences were observed regarding the weight of the right and left breasts treated with DMBA compared to negative controls. Treatment with CPA, CIT, and LP-CIT reduced the weight of both breasts, with better results for liposomal citrinin. Furthermore, CPA, CIT, and LP-CIT presented genotoxic effects for tumor, blood, bone marrow, and liver cells, although less DNA damage was observed for LP-CIT compared to CIT and CPA. Healthy cell damage induced by LP-CIT was repaired during treatment, unlike CPA, which caused clastogenic effects. Thus, LP-CIT showed advantages for its use as a model of nanosystems for antitumor studies.
PubMed: 38399235
DOI: 10.3390/pharmaceutics16020174 -
Reproductive Toxicology (Elmsford, N.Y.) Mar 2024Fetal hepatic dimethylbenz(a)anthracene (DMBA) biotransformation is not defined, thus, this study investigated whether the fetal liver metabolizes DMBA and differs with...
Fetal hepatic dimethylbenz(a)anthracene (DMBA) biotransformation is not defined, thus, this study investigated whether the fetal liver metabolizes DMBA and differs with biological sex. KK.Cg-a/a (lean; n = 20) or KK.Cg-Ay/J (obese; n = 20) pregnant mice were exposed to corn oil (CT) or DMBA (1 mg/kg bw/day) by intraperitoneal injection (n = 10/treatment) from gestation day 7-14. Postnatal day 2 male or female offspring livers were collected. Total RNA (n = 6) and protein (n = 6) were analyzed via a PCR-based array or LC-MS/MS, respectively. The level of Mgst3 was lower (P < 0.05) in livers of female compared to male offspring. Furthermore, in utero DMBA exposure increased (P < 0.1) Cyp2c29 and Gpx3 levels (P < 0.05) in female offspring. In male offspring, the abundance of Ahr, Comt (P < 0.1), Alox5, and Asna1 (P < 0.05) decreased due to DMBA exposure. Female and male offspring had 34 and 21 hepatic proteins altered (P < 0.05) by in utero DMBA exposure, respectively. Opposing patterns for hepatic CD81 and KRT78 occurred, being decreased in females but increased in males, while YWHAG was decreased by DMBA exposure in both. Functional KEGG pathway analysis identified enrichment of 26 and 13 hepatic metabolic proteins in male and female offspring, respectively, due to in utero DMBA exposure. In silico transcription factor analysis of differentially expressed proteins predicted involvement of female NRF1 but male AHR. Thus, hepatic biological sex differences and capacity to respond to toxicants in utero are supported.
Topics: Pregnancy; Mice; Female; Male; Animals; 9,10-Dimethyl-1,2-benzanthracene; Chromatography, Liquid; Sex Characteristics; Tandem Mass Spectrometry; Liver
PubMed: 38307155
DOI: 10.1016/j.reprotox.2024.108553