Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.
Animals ; Carcinogenesis/pathology* ; Cattle ; Cell Cycle Proteins/metabolism* ; Cell Proliferation/drug effects* ; Cell Transformation, Neoplastic/pathology* ; Cells, Cultured ; Epithelial Cells/pathology* ; Female ; Histone Deacetylase 2/metabolism* ; Imatinib Mesylate/pharmacology* ; Interferon-gamma/pharmacology* ; Mammary Glands, Animal/pathology* ; Mammary Neoplasms, Experimental/pathology* ; Proto-Oncogene Proteins c-abl/metabolism* ; Signal Transduction ; Valproic Acid/pharmacology*

Phenolics, as the main bioactive compounds in tea, have been suggested to have potential in the prevention of various human diseases. However, little is known about phenolics and their bioactivity in Zhangping Narcissue tea cake which is considered the most special kind of oolong tea. To unveil its bioactivity, three phenolic-enriched extracts were obtained from Zhangping Narcissue tea cake using ethyl acetate, n-butanol, and water. Their main chemical compositions and in vitro bioactivity were analyzed by high-performance liquid chromatography (HPLC) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The ethyl acetate fraction (ZEF) consisted of higher content of phenolics, flavonoids, procyanidins, and catechin monomers (including epigallocatechin gallate (EGCG), epicatechin gallate (ECG), and gallocatechin gallate (GCG)) than n-butanol fraction (ZBF) and water fraction (ZWF). ZEF exhibited the strongest antioxidant capacity in vitro due to its abundant bioactive compounds. This was validated by Pearson correlation and hierarchical clustering analyses. ZEF also showed a remarkable inhibition on the growth, migration, and invasion of 4T1 murine breast cancer cells.
Animals ; Antineoplastic Agents, Phytogenic/pharmacology* ; Antioxidants/pharmacology* ; Camellia sinensis/chemistry* ; Cell Line, Tumor ; Cell Movement/drug effects* ; Cell Proliferation/drug effects* ; Female ; Mammary Neoplasms, Experimental/pathology* ; Mice ; Neoplasm Metastasis ; Phenols/pharmacology* ; Plant Extracts/pharmacology*

OBJECTIVETo evaluate the inhibitory effect of genistin combined with anastrozole on the growth and apoptosis of breast tumor tissue, and to study their anti-cancer mechanism by using the model of 7,12-dimethylbenz [alpha] anthracene (DMBA)-induced mammary tumors following ovariectomy in Sprague-Dawley (SD) rats.

METHODSThe DMBA induced postmenopausal SD rats were randomly divided into the control group, the genistein group, the anastrozole group, and the genistein combined with anastrozole group. The growth of tumors was observed in each group. The proliferation index and apoptosis index of tumor cells were determined. Moreover, estradiol (E2) and 17beta-HSD1 mRNA levels were determined by ELISA and RT-PCR respectively.

RESULTSThe tumor growth was inhibited in the genistein group and the anastrozole group. The inhibitory ratio was significantly higher in the genistein combined with anastrozole group (P < 0.05). Compared with the control group, levels of E2 and 17beta-HSD1 mRNA decreased more significantly in the genistein combined with anastrozole group (P < 0.05).

CONCLUSIONSGenistein could suppress the growth of mammary tumors in postmenopausal rats. It showed synergistic effect when combined with anastrozole, which resulted in reduced levels of E2 and 17beta-HSD1 mRNA. It had inhibitory effect on the growth of breast tumors.

17-Hydroxysteroid Dehydrogenases ; metabolism ; Animals ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Estradiol ; metabolism ; Female ; Genistein ; administration & dosage ; pharmacology ; Mammary Neoplasms, Experimental ; chemically induced ; pathology ; Nitriles ; administration & dosage ; pharmacology ; Ovariectomy ; Postmenopause ; Rats ; Rats, Sprague-Dawley ; Triazoles ; administration & dosage ; pharmacology

OBJECTIVETo develop a novel thermal treatment modality against metastatic tumor, and to verify the hypothesis that the extent of tumor angiogenesis damage and tumor cell necrosis, accompanied with immune suppression cells relief is deterministic to enhance therapeutic effect in the thermal treatment.

METHODSThe thermal treatment system was developed in our laboratory. The treatment including hyperthermia and alternate treatment, were locally applied to 4T1 murine mammary carcinoma. The extent of tumor necrosis was examined. Further investigations were performed to study the changes of MDSCs in peripheral blood and spleen.

RESULTSThe alternate treatment caused more damage to tumor microvasculature and tumor cell necrosis. Immunosuppression cells significantly reduced in peripheral blood and spleen. Moreover, it highly increased the survival rate of tumor-bearing mice.

CONCLUSIONSThe greatest destruction of primary tumor induced by the alternate treatment led to a relief of immune suppression in tumor bearing mice, and significantly increased therapeutic effect, especially for metastatic tumor.

Animals ; Female ; Hyperthermia, Induced ; methods ; Mammary Neoplasms, Experimental ; immunology ; pathology ; therapy ; Mice ; Mice, Inbred BALB C ; Myeloid Cells ; immunology ; Neoplasm Metastasis

In order to investigate the anti-proliferative effects of triptolide (TP) on 4T1 mice breast cancer cell line in vitro and in mouse model, as well as the possible mechanisms, we detected the effect of TP on cell proliferation by MTT assay or Crystal Violet Staining in our research. Flowcytometry combined with FITC-Annexin V/PI staining were used for detecting TP induced 4T1 cell apoptosis. The protein expression of ERalpha, p-ERalpha, ERbeta, p-ERbeta, ERK, p-ERK, p38, p-p38, SAPK/JNK, and p-SAPK/JNK was tested by western blotting. We also compare TP with chemotherapy drug doxorubicin in 4T1 tumor bearing BLAB/c mice model, the Xenogen bioluminescence imaging, H&E, and IHC result indicated that TP exhibits an anticancer proliferation activity. As a result, TP in 100, 10, 1, 0.1 micromol x L(-1), all inhibited the proliferation of 4T1 cells by MTT assay and Crystal Violet Staining. TP which concentrations is 10, 1, 0.1 micromol x L(-1) could induce the apoptosis of 4T1 cells and reduce the cell proliferation. TP in 200 microg x kg(-1) could inhibit the tumor growth in vivo. The anticancer proliferation of TP was involved in its effect on reducing expression of ERalpha, p-ERalpha, ERbeta, and p-ERbeta, but nothing to do with the activation of MAPK signaling pathway.
Animals ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; Diterpenes ; pharmacology ; therapeutic use ; Down-Regulation ; drug effects ; Epoxy Compounds ; pharmacology ; therapeutic use ; Female ; Lung Neoplasms ; secondary ; Mammary Neoplasms, Experimental ; drug therapy ; metabolism ; pathology ; Mice ; Mice, Inbred BALB C ; Phenanthrenes ; pharmacology ; therapeutic use ; Phosphorylation ; drug effects ; Receptors, Estrogen ; metabolism ; Tumor Burden ; drug effects

OBJECTIVETo explore the effect of ricin temperature response gel on breast cancer and its regulatory effect on immune function in rats.

METHODSRicin was purified by chromatography and identified by immunoblotting. The rat subcutaneously transplanted breast cancer model was established. Forty model rats with a tumor diameter of about 3.0 cm were subjected to the study. They were randomized into four groups equally: the model group and three treated groups (blank gel, ricin, ricin-gel) were administered with blank gel, ricin, and ricin temperature response gel via percutaneous intratumor injection, respectively. The tumor was isolated 10 days later for the estimation of tumor inhibition rate (TIR) by weighing, pathologic examination, and detection of tumor apoptosis-associated genes bcl-2 and bax with semiquantitative RT-PCR. Also, peripheral blood was obtained to test T-lymphocyte subsets, the killing function of lymphocytes, and the contents of tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). The outcomes were compared between groups.

RESULTSThe TIR in the ricin-gel group was 61.8%, with the pathologic examination showing extensive tumor tissue necrosis. Compared with the model group, after ricin temperature response gel treatment, bcl-2 expression was down-regulated, bax expression was up-regulated, CD4+ lymphocytes and CD4+/CD8+ ratio in peripheral blood were increased, the killing function of lymphocytes was enhanced, and the contents of TNF-α and IL-2 were elevated (P < 0.05 or P < 0.01).

CONCLUSIONIntratumor injection of ricin temperature-responsive gel showed significant antitumor effect on breast cancer and could enhance the immune function in the tumor-bearing rat.

Animals ; Antineoplastic Agents ; administration & dosage ; Apoptosis ; drug effects ; CD4-CD8 Ratio ; Disease Models, Animal ; Female ; Gels ; therapeutic use ; Immunohistochemistry ; Immunomodulation ; drug effects ; Injections, Intralesional ; Interleukin-2 ; immunology ; metabolism ; Mammary Neoplasms, Experimental ; drug therapy ; immunology ; pathology ; Random Allocation ; Rats ; Rats, Wistar ; Ricin ; administration & dosage ; Sensitivity and Specificity ; Temperature ; Tumor Necrosis Factor-alpha ; immunology ; metabolism

No abstract available.
Animals ; Female ; Lymphatic Metastasis/*pathology ; Magnetic Resonance Imaging/*methods ; Mammary Neoplasms, Experimental/*pathology

OBJECTIVETo investigate the apoptosis in MA-891 cells induced by different concentrations of As2O3 and to study its influence on the activity of telomerase and telomerase mTERT-mRNA, which provide theoretical and experimental basis for breast carcinoma.

METHODThe MA-891 breast carcinoma cell lines were used as the object. Different concentration of As2O3 was cultivated with MA-891 cells, and the growth inhibition of MA-891 cells was analyzed by MTT. The rate of apoptosis in MA-891 cells was detected by flow cytometry. The telomerase activity was determined by TRAP-PAGE-SILVER staining and was analyzed by specific soft ware. The expression mTERT-mRNA was examined by RT-PCR assay in untreated and As2O3-treated cells.

RESULTAs2O3 could inhibit the growth of MA-891 cells remarkably; the IC50 value of As2O3 for MA-891 was 9.68 micromol x L(-1) and 5.50 micromol x L(-1) respectively during 24,48 h. The percentage of the apoptosis in MA-891 cells was 30.21%, 48.26%, 57.43%, as the cells were treated with 5, 10, 20 micromol x L(-1) As2O3 for 24 hours. Treated with As2O3 for 24 hand 48 h, the telomerase activity of MA-891 cells was inhibited remarkably, which showed obvious time and concentration dependence. The mTERT-mRNA expression of MA-891 cells were significantly inhibited when treated with As2O3 for 24 h and 48h.

CONCLUSIONAs2O3 could remarkably inhibit the growth of MA-891 cells and could promote the apoptosis of the cells. Treated with As2O3, the activities of telomerase and telomerase mTERT-mRNA were inhibited remarkably and were obvious dosage-effect correlation.

Animals ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Arsenicals ; pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Mammary Neoplasms, Experimental ; drug therapy ; pathology ; Mice ; Oxides ; pharmacology ; Telomerase ; genetics

OBJECTIVE: This experiment aims to determine the diagnostic value of diffusion-weighted imaging (DWI) in the differentiation of axillary inflammatory lymph nodes from metastatic lymph nodes in rabbit models in comparison with conventional magnetic resonance imaging (MRI). MATERIALS AND METHODS: Conventional MRI and DWI were performed at 4 weeks after successful inoculation into the forty female New Zealand white rabbits' mammary glands. The size-based and signal-intensity-based criteria and the relative apparent diffusion coefficient (rADC) value were compared between the axillary inflammatory lymph nodes and metastatic lymph nodes, with histopathological findings as the reference standard. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of the aforementioned criteria and rADC value in differentiating the axillary inflammatory lymph nodes from metastatic lymph nodes. RESULTS: Thirty-two axillary inflammatory lymph nodes and 46 metastatic ones were successfully isolated and taken into pathological analysis. The differences of the aforementioned criteria between the two groups were not statistically significant (p > 0.05). However, the rADC value of the inflammatory lymph nodes (0.9 +/- 0.14) was higher than that of metastatic ones (0.7 +/- 0.18), with significant difference (p = 0.016). When the rADC value was chosen as 0.80, the area under the ROC curve is greater than all other criteria, and the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiating two groups were 86.2%, 79.3%, 81.2%, 84.2%, and 85.6%, respectively. CONCLUSION: Diffusion-weighted imaging is a promising new technique for differentiating axillary inflammatory lymph nodes from metastatic lymph nodes. Compared with routine magnetic resonance sequences, DWI could provide more useful physiological and functional information for diagnosis.
Animals ; Axilla ; Diagnosis, Differential ; Diffusion Magnetic Resonance Imaging ; Female ; Inflammation/pathology ; Lymphatic Metastasis/*pathology ; Magnetic Resonance Imaging/*methods ; Mammary Neoplasms, Experimental/*pathology ; ROC Curve ; Rabbits ; Sensitivity and Specificity

OBJECTIVETo investigate the anticancer and anti-metastatic effect of Ajuga decumbens extraction (HBG) on breast cancer and to clarify the effect of HBG on MMPs and TIMPs.

METHODThe antitumor and antimetastic effect of HBG was determined using orthotopic 4T1 breast cancer mouse model. Western blot analysis was employed to detect the expression of associated proteins in breast cancer metastasis.

RESULTAdministration with 50-200 mg x kg(-1) doses of HBG significantly reduced the tumor weight, tumor volume and numbers of lung tumor nodules in a dose-dependent manner. Tumor metastasis correlated proteins were altered following HBG treatment, MMP-2 and MMP-9 were down-regulated while TIMP-1 and TIMP-2 were up-regulated.

CONCLUSIONHBG showed anticancer and antimetastatic effect towards breast cancer through regulating the expression of MMPs and TIMPs. These data sustain our contention that HBG might be used as a potential therapeutic agent.

Ajuga ; Animals ; Female ; Mammary Neoplasms, Experimental ; chemistry ; drug therapy ; pathology ; Matrix Metalloproteinase 2 ; analysis ; Matrix Metalloproteinase 9 ; analysis ; Metalloproteases ; analysis ; Mice ; Mice, Inbred BALB C ; Neoplasm Invasiveness ; Neoplasm Metastasis ; prevention & control ; Phytotherapy ; Plant Extracts ; therapeutic use ; Tissue Inhibitor of Metalloproteinase-1 ; analysis ; Tissue Inhibitor of Metalloproteinase-2 ; analysis ; Tissue Inhibitor of Metalloproteinases ; analysis