Using a cell-based high-throughput screen designed to detect small chemical compounds that inhibit cell growth and survival, we identified three structurally related compounds, 21A8, 21H7, and 65D4, with differential activity on cancer versus normal cells. Introduction of structural modifications yielded compound M-110, which inhibits the proliferation of prostate cancer cell lines with IC 50 s of 0.6 to 0.9 μmol/L, with no activity on normal human peripheral blood mononuclear cells up to 40 μmol/L. Screening of 261 recombinant kinases and subsequent analysis revealed that M-110 is a selective inhibitor of the PIM kinase family, with preference for PIM-3. The prostate cancer cell line DU-145 and the pancreatic cancer cell line MiaPaCa2 constitutively express activated STAT3 (pSTAT3 , we used PIM-1-, PIM-2-, or PIM-3-specific siRNA and showed that knockdown of PIM-3, but not of PIM-1 or PIM-2, in DU-145 cells results in a significant downregulation of pSTAT3 Tyr705. The phosphorylation of STAT5 on Tyr694 in 22Rv1 cells is not affected by M-110 or SGI-1776, suggesting specificity for pSTAT3 Tyr705 . These results identify a novel role for PIM-3 kinase as a positive regulator of STAT3 signaling and suggest that PIM-3 inhibitors cause growth inhibition of cancer cells by downregulating the expression of pSTAT3 Tyr705
Purpose: While numerous biology-driven subtypes have been described in metastatic castration-resistant prostate cancer (mCRPC), unsupervised molecular subtyping based on gene expression has been less studied, especially using large cohorts. Thus, we sought to identify the intrinsic molecular subtypes of mCRPC and assess molecular and clinical correlates in the largest combined cohort of mCRPC samples with gene expression data available to date. Methods: We combined and batch effect corrected gene expression data from four mCRPC cohorts from the Fred Hutchinson Cancer Research Center (FHCRC, N=157), a small-cell neuroendocrine prostate cancer (SCNC)-enriched cohort from Weill Cornell Medicine (WCM, N=49), and cohorts from the Stand Up 2 Cancer/Prostate Cancer Foundation East Coast Dream Team (ECDT, N=266) and the West Coast Dream Team (WCDT, N=162). Results: Hierarchical clustering of RNA-seq data from these 634 mCRPC samples identified two distinct adenocarcinoma subtypes, one of which (adeno-immune) was characterized by higher gene expression of immune pathways, higher CIBERSORTx immune scores, diminished ASI benefit, and non-lymph node metastasis tropism compared to an adeno-classic subtype. We also identified two distinct subtypes with enrichment for a neuroendocrine (NE) phenotype, including an NE-liver subgroup characterized by liver metastasis tropism, PTEN loss, and APC and SPOP mutations compared to an NE-classic subgroup. Conclusion: Our results emphasize the heterogeneity of mCRPC beyond currently accepted molecular phenotypes, and suggests that future studies should consider incorporating transcriptome-wide profiling in order to better understand how these differences impact treatment responses and outcomes.
Abstract. Breast cancer is a serious disease in the uS. numerous risk factors have been linked to this disease. the safety of using growth promoters, such as zeranol, remains under debate due to the lack of sufficient in vitro and in vivo evidence. using celltiter 96™ aqueous non-radioactive cell proliferation assay, real-time pcr and Western blot analysis, we evaluated the effects of sera harvested from experimental and control heifers before and after one month of zeranol implantation on the growth of human breast cancer cell line mcF-7 as well as the involved mechanisms. We found that sera harvested from the heifers following one month of zeranol implantation were more mitogenically potent in stimulating the proliferation of mcF-7 cells when compared to sera harvested from the same heifers before zeranol implantation and the control heifers. Further investigation found that dextran-coated charcoal suppressed the stimulating effect of the sera on mcF-7 cell growth. the mechanisms involved in the mcF-7 cell proliferation stimulated by zeranol-containing sera may include up-regulation of cyclin d1 and down-regulation of p53 and p21 expression at the mrna and protein levels in the cells. the results suggest that the consumption of beef products containing biologically active residues of zeranol or its metabolites is a risk linked to breast cancer development. Further investigation is required in order to clarify this critical issue.
Epidemiological studies have suggested that there are many risk factors associated with breast cancer. Silencing tumor suppressor genes through epigenetic alterations play critical roles in breast cancer initiation, promotion and progression. As a growth promoter, Zeranol (Z) has been approved by the FDA and is widely used to enhance the growth of beef cattle in the United States. However, the safety of Z use as a growth promoter is still under debate. In order to provide more evidence to clarify this critical health issue, the current study investigated the effect of Z on the proliferation of primary cultured human normal and cancerous breast epithelial cells (PCHNBECs and PCHBCECs, respectively) isolated from the same patient using MTS assay, RT-PCR and Western blot analysis. We also conducted an investigation regarding the mechanisms that might be involved. Our results show that Z is more potent to stimulate PCHBCEC growth than PCHNBEC growth. The stimulatory effects of Z on PCHBCECs and PCHBCECs may be mediated by its down-regulating expression of the tumor suppressor gene p53 at the mRNA and protein levels. Further investigation showed that the expression of DNA methylatransferase 1 mRNA and protein levels is up-regulated by treatment with Z in PCHBCECs as compared to PCHNBECs, which suggests a role of Z in epigenetic modification involved in the regulation of p53 gene expression in PCHBCECs. Our experimental results imply the potentially adverse health effect of Z in breast cancer development. Further study is continuing in our laboratory.
Guidelines for venous thromboembolism (VTE) prophylaxis recommend appropriate risk stratification using risk estimation models as high risk or low risk followed by initiation of chemical or mechanical prophylaxis, respectively. We explored adherence to guidelines on the basis of the documentation of VTE prophylaxis. A retrospective medical record review of 437 consecutive adult patients (≥18 years) admitted to general medical wards under medicine service between January 1, 2015, and March 1, 2015, was performed. The primary outcome was appropriateness of risk stratification using the Padua Prediction Score. Secondary outcomes were appropriateness of type of prophylaxis (chemical vs mechanical) and cost-benefit analysis. We observed appropriate stratification based on the documented risk (compared with the calculated risk) in 54.9% of the patients (40.8% with low risk vs 72.1% with high risk; P<.001). Overall, 182 of 240 low-risk patients received unnecessary chemical prophylaxis, whereas 23 of 197 high-risk patients without contraindications for chemical prophylaxis received mechanical or no prophylaxis. No clinical VTE events were noted in the patients inappropriately assigned to mechanical or no prophylaxis. Also, 67.3% of patients with both low documented and low calculated risk and 74.5% of patients with low documented and high calculated risk received chemical prophylaxis, consistent with a tendency toward overtreatment. A total of 4068 annualized patient-days ($77,652/y) of inappropriate chemical prophylaxis were administered. In conclusion, estimation of the risk of VTE based on clinical impression was not congruent with the risk calculated using risk prediction models and was associated with a tendency toward overtreatment. These data support the inclusion of VTE risk calculators in electronic health record systems.
Abstract. Breast cancer and obesity are serious health problems and their relationship has been studied for many years. Leptin is mainly secreted by adipocytes and plays a key role in breast cancer development. Leptin expression is up-regulated in obese individuals and promotes breast cancer cell growth. On the other hand, exposure to environmental estrogens has been found to be directly related to breast cancer. Zeranol (Z) is a non-steroidal anabolic growth promoter used in the beef industry in the US. This study focused on the evaluation of Z and Z-containing sera (ZS) and its adverse health risk to human consumption of Z-containing meat produced from Z-implanted beef cattle. We hypothesized that Z increases the risk of breast neoplasia in women, particularly in obese women. A cell proliferation assay, ELISA analysis, RT-PCR and Western blot analysis were conducted. Our study demonstrated that Z and ZS collected from Z-implanted heifers stimulated the proliferation of primary cultured human normal breast epithelial cells (HNBECs) by up-regulating cyclin D1 expression. Leptin increased the sensitivity of HNBECs to Z, and Z increased the ability of HNBECs to secrete leptin. These results suggest an interaction between leptin and Z in HNBECs. Furthermore, Z may play a role in leptin-induced breast neoplasia.
Abstract. Among many risk factors of breast cancer, estrogens and non-estrogenic endocrine disruptors are considered to play critical roles in human breast carcinogenesis. Zeranol (Z) is a non-steroidal agent with potent estrogenic activity and has been widely used as an FDA approved beef growth promoter in the US. Recently, concerns have been raised about the potential adverse health risk by consumption of products containing biologically active Z and its metabolites. By utilizing cell proliferation assay, soft agar assay, quantitative real-time PCR and Western blotting analysis, we examined the potentially tumorigenic activity of bio-active Z containing sera harvested from heifers two months post Z-implantation and the underlying mechanisms. Our results showed that the growth of MCF-10A exposed to 0.2, 1 and 5% Z-containing serum (ZS) treatment for 3 weeks was 1.3, 1.75 and 1.8-fold faster compared to that of the control sera. After further investigation, we found that ZS increased cyclin D1 and decreased p53 expression at the mRNA and protein levels in MCF-10A compared to the controls. More importantly, treatment of 1% Z-containing sera for 21 days stimulated MCF-10A cells anchorage-independent colony formation in soft agar which illustrates its capability of inducing human normal breast epithelial cell neoplastic transformation. Our experimental results suggest that longterm exposure of low levels of Z and its metabolites contained in beef products might be a potential risk factor in human breast cancer initiation and development.
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