Estrogen receptor signaling regulates the expression of the breast tumor kinase in breast cancer cells.

BACKGROUND: BRK is, a non-receptor tyrosine kinase, overexpressed in approximately 85% of human invasive ductal breast tumors. It is not clear whether BRK expression correlates with breast cancer subtypes, or the expression has prognostic or diagnostic significance. Herein, we investigated the correlation of BRK with any breast cancer subtypes and clinicopathological significance of BRK expression in breast cancer. METHODS: In this study, we examined BRK expression in 120 breast tumor samples and 29 breast cancer cell lines to explore the positive correlation between BRK and the expression of ERα. We used immunohistochemistry, RT-PCR, and immunoblotting to analyse our experimental samples. RESULT: We demonstrate that estrogen induces BRK gene and protein expression in ER+ breast cancer cells. Over-expression of ERα in the ER-negative breast cancer cell line increased BRK expression, and knock-down of ESR1 in MCF7 cells reduced BRK levels. Further, we provide evidence that BRK is regulated by ERα signaling and the presence of ER antagonists (tamoxifen and fulvestrant) reduce the expression of BRK in ER-positive breast cancer cells. Finally, we demonstrate that the overall survival of ER-positive breast cancer patients is poor when their cancers express high levels of BRK. CONCLUSION: Our data indicate that BRK is a prognostic marker for ER+ breast cancers and provide a strong rationale for targeting BRK to improve patients' survival.

Breast cancer in Africa: prevalence, treatment options, herbal medicines, and socioeconomic determinants.

Breast cancer is the leading cause of cancer-related deaths in women worldwide. GLOBOCAN estimated about 1.7 million new cases of breast cancer diagnoses worldwide and about 522,000 deaths in 2012. The burden of breast cancer mortality lies in the developing low-income and middle-income countries, where about 70% of such deaths occur. The incidence of breast cancer is also rising in low-income and middle-income countries in Africa as trend towards urbanization, and adoption of Western lifestyles increases. In general, the triple-negative breast cancer (TNBC) subtype tends to be frequent in women of African ancestry. What are the factors contributing to this prevalence? Are there genetic predispositions to TNBC in African women? This review addresses these questions and provides an update on the incidence, survival, and mortality of breast cancer in Africans, with a focus on sub-Saharan Africans. We have also addressed factors that could account for ethical disparities in incidence and mortality. Further, we have highlighted challenges associated with access to essential drug and to healthcare treatment in some African countries and outlined alternative/herbal treatment methods that are increasingly implemented in Africa and other developing nations.

Caffeine-supplemented diet modulates oxidative stress markers and improves locomotor behavior in the lobster cockroach Nauphoeta cinerea.

The effects of caffeine supplementation is well documented in conventional animal models, however, in the lobster cockroaches Nauphoeta cinerea, they have not been reported. Thus, the aim of this study was to investigate the locomotor behavior and biochemical endpoints in the head of the nymphs of N. cinerea following 60 days exposure to food supplemented with 0, 0.5, 1.0, 2.5, 5.0 and 10.0 mg of caffeine/g of diet. The analysis of the locomotor behavior using the video-tracking software, Any-maze, for 12 min revealed that caffeine supplementation caused significant behavioral improvement. There was increase in distance travelled, velocity, frequency of rotation and turn angle (stereotypical behavior such as circling movements), and this was supported by the representative track plots of the path travelled by cockroaches in the open-field arena. In addition, caffeine supplementation markedly increased total thiol and non-protein thiol glutathione (GSH) levels in the heads of cockroaches, and this was in parallel with significant reduction of lipid peroxidation and free Fe(II) content. Taking together, our results indicate that long-term caffeine supplementation may exert preventive effects against oxidative stress and support the use of N. cinerea as an efficient alternative model to assess the efficacy of food molecules.

Repression of Fyn-related kinase in breast cancer cells is associated with promoter site-specific CpG methylation.

The triple-negative breast cancer subtype is highly aggressive and has no defined therapeutic target. Fyn-related kinase (FRK) is a non-receptor tyrosine kinase, reported to be downregulated in breast cancer and gliomas, where it is suggested to have tumor suppressor activity. We examined the expression profile of FRK in a panel of 40 breast cancer cells representing all the major subtypes, as well as in 4 non-malignant mammary epithelial cell lines. We found that FRK expression was significantly repressed in a proportion of basal B breast cancer cell lines. We then determined the mechanism of suppression of FRK in FRK-low or negative cell lines. In silico analyses of the FRK promoter region led to the identification of at least 17 CpG sites. Bisulphite sequencing of the promoter region revealed that two of these sites were consistently methylated in FRK-low/negative cell lines and especially in the basal B breast cancer subtype. We further show that treatment of these cells with histone deacetylase inhibitors, Entinostat and Mocetinostat' promoted re-expression of FRK mRNA and protein. Further, using luciferase reporter assays, we show that both GATA3-binding protein FOG1 and constitutively active STAT5A increased the activity of FRK promoter. Together, our results present the first evidence that site-specific promoter methylation contributes to the repression of FRK more so in basal B breast cancers. Our study also highlights the potential clinical significance of targeting FRK using epigenetic drugs specifically in basal B breast cancers which are usually triple negative and very aggressive.

FRK inhibits breast cancer cell migration and invasion by suppressing epithelial-mesenchymal transition.

The human fyn-related kinase (FRK) is a non-receptor tyrosine kinase known to have tumor suppressor activity in breast cancer cells. However, its mechanism of action has not been fully characterized. We generated FRK-stable MDA-MB-231 breast cancer cell lines and analyzed the effect on cell proliferation, migration, and invasiveness. We also used kinome analysis to identify potential FRK-regulated signaling pathways. We employed both immunoblotting and RT-PCR to identify/validate FRK-regulated targets (proteins and genes) in these cells. Finally, we interrogated the TCGA and GENT gene expression databases to determine the correlation between the expression of FRK and epithelial/mesenchymal markers. We observed that FRK overexpression suppressed cell proliferation, migration, and invasiveness, inhibited various JAK/STAT, MAPK and Akt signaling pathways, and suppressed the expression of some STAT3 target genes. Also, FRK overexpression increased the expression of epithelial markers including E-cadherin mRNA and down-regulated the transcript levels of vimentin, fibronectin, and slug. Finally, we observed an inverse correlation between FRK expression and mesenchymal markers in a large cohort of breast cancer cells. Our data, therefore, suggests that FRK represses cell proliferation, migration and invasiveness by suppressing epithelial to mesenchymal transition.

Influence of gallic acid on oxidative stress-linked streptozotocin-induced pancreatic dysfunction in diabetic rats.

BACKGROUND: Recent advances in diabetic research involve the evaluation of agents that can regenerate or reverse pancreatic dysfunction. Although gallic acid (GA) has been reported as an antidiabetic agent, its ability to directly reverse altered biochemical parameters in diabetic pancreas has not been demonstrated. METHODS: Male albino rats with diabetes induced by the administration of streptozotocin (STZ) (50 mg/kg, intraperitoneally) were treated with oral administration of GA. Antioxidants (enzymatic and non-enzymatic), purinergic enzymes, δ-aminolevulinic acid dehydratase and lactate dehydrogenase were evaluated in the pancreas of both diabetic and nondiabetic animals. RESULTS: The pharmacological effect of GA was accompanied by a restoration of the observed decreased levels of vitamin C and reduced glutathione in the pancreas of STZ-treated rats. GA also caused a marked reduction in the high levels of thiobarbituric acid reactive substances observed in the STZ-induced diabetic group. Furthermore, GA also improves the free radical scavenging property, Fe2+ chelating ability and Fe3+ reducing property of the pancreas of diabetic animals. Finally, the inhibition of pancreatic catalase, glutathione S-transferase, δ-aminolevulinic acid dehydratase and lactate dehydrogenase and increased activity of purinergic enzymes accompanied by hyperglycemia were prevented by GA in the pancreas. CONCLUSIONS: The direct influence and consequent restoration of altered biochemical conditions in the pancreatic tissue of diabetic animal models by GA makes it a promising antidiabetic candidate especially in pancreatic cell regeneration.

Effects of Tapinanthus globiferus and Zanthoxylum zanthoxyloides extracts on human leukocytes in vitro.

OBJECTIVE: This study aimed at investigating the genotoxicity and cytotoxicity effect of Tapinanthus globiferus and Zanthoxylum zanthoxyloides to human leukocytes. In addition, the reductive potential and the chemical composition of the two plant extracts were also determined. MATERIALS AND METHODS: Human leukocytes were obtained from healthy volunteer donors. The genotoxicity and cytotoxicity of T. globiferus and Z. zanthoxyloides were assessed using the comet assay and trypan blue exclusion, respectively. The antioxidant activity of the plant extracts was evaluated by the reducing power assay. Furthermore, high-performance liquid chromatography-diode array detector was used to characterize and quantify the constituents of these plants. RESULTS: T. globiferus (10-150 µg/mL) was neither genotoxic nor cytotoxic at the concentrations tested, suggesting that it can be consumed safely at relatively high concentrations. However, Z. zanthoxyloides showed cytoxicity and genotoxicity to human leukocytes at the highest concentration tested (150 µg/mL). In addition, the total reducing power of T. globiferus was found higher than Z. zanthoxyloides in potassium ferricyanide reduction. Both plants extract contained flavonoids (rutin and quercetin) and phenolic acids (chlorogenic and caffeic). CONCLUSION: The results obtained support the fact that some caution should be paid regarding the dosage and the frequency of use of Z. zanthoxyloides extract.