Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer.

The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.

Religious Beliefs Against Smoking Among Black and White Urban Youth.

This study explores the relation of religiosity to cigarette smoking in a sample of 4776 Black versus White adolescents. Findings show that Black adolescents have significantly stronger religious beliefs against smoking than do White students. Further, teens with strong or very strong religious beliefs are less likely to have smoked. The protective effect of religious beliefs against smoking was stronger for Whites than for Blacks. These findings suggest that efforts in the Black religious community to prevent cigarette smoking have been somewhat successful. Similar efforts in the White community might help stem the tide of tobacco use among White teens.

Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression.

High expression of the oncoprotein Myc has been linked to poor outcome in human tumors. Although MYC gene amplification and translocations have been observed, this can explain Myc overexpression in only a subset of human tumors. Myc expression is in part controlled by its protein stability, which can be regulated by phosphorylation at threonine 58 (T58) and serine 62 (S62). We now report that Myc protein stability is increased in a number of breast cancer cell lines and this correlates with increased phosphorylation at S62 and decreased phosphorylation at T58. Moreover, we find this same shift in phosphorylation in primary breast cancers. The signaling cascade that controls phosphorylation at T58 and S62 is coordinated by the scaffold protein Axin1. We therefore examined Axin1 in breast cancer and report decreased AXIN1 expression and a shift in the ratio of expression of two naturally occurring AXIN1 splice variants. We demonstrate that this contributes to increased Myc protein stability, altered phosphorylation at S62 and T58, and increased oncogenic activity of Myc in breast cancer. Thus, our results reveal an important mode of Myc activation in human breast cancer and a mechanism contributing to Myc deregulation involving unique insight into inactivation of the Axin1 tumor suppressor in breast cancer.

Characterization of the DNA binding specificity of Shelterin complexes.

The Shelterin complex associates with telomeres and plays an essential role in telomere protection and telomerase regulation. In its most abundant form, the complex is composed of six core components: TRF1, TRF2, POT1, TIN2, TPP1 and RAP1. Of these subunits, three can interact directly with either single-stranded (POT1) or double-stranded (TRF1, TRF2) telomeric DNA. In this report, we have developed assays to measure the DNA binding activity of Shelterin complexes in human cell extracts. With these assays, we have characterized the composition and DNA binding specificity of two Shelterin complexes: a 6-member complex that contains all six core components and a second complex that lacks TRF1. Our results show that both of these complexes bind with high affinity (K(D) = 1.3-1.5 × 10(-9) M) and selectively to ds/ss-DNA junctions that carry both a binding site for POT1 (ss-TTAGGGTTAG) and a binding site for the SANT/Myb domain of TRF1 or TRF2 (ds-TTAGGGTTA). This DNA binding specificity suggests the preferential recruitment of these complexes to areas of the telomere where ss- and ds-DNA are in close proximity, such as the 3'-telomeric overhang, telomeric DNA bubbles and the D-loop at the base of T-loops.

Gender differences in the effects of parental underestimation of youths' secondary exposure to community violence.

Secondary exposure to community violence is particularly detrimental for male youths, who disproportionately report witnessing community violence and suffering associated trauma-related symptoms. Yet, few studies have investigated whether parents perceive and report similar gender disparities among youths. In addition, few studies have examined the potentially negative effects of parent-child discord as to the youth's level of exposure to violence, or whether these effects vary across gender. Therefore, this study investigated whether differences between parents' and youths' reports of youths' exposure to violence, and the consequences of such reporting discord, varied across the gender of the youth informant. Participants were adolescents aged approximately 12 and 15 years at baseline (N = 1,517; 51 % female). Descriptive analyses indicated that male youths reported significantly higher levels of exposure to violence than female youths, but parents similarly under-reported their male and female children's experiences with violence. Hierarchical analyses indicated that parental underestimation of youths' exposure to violence had negative consequences. Moreover, significant interaction effects demonstrated that only females responded to reporting discord with internalizing problems. Conversely, both male and female youths responded to reporting discord with externalizing problems and offending. The results suggest that while parent-child discord is associated with negative outcomes for both male and female youths, discord may be disproportionately associated with negative outcomes among young females. The findings speak to the utility of examining the correlates and consequences of exposure to violence from a "gendered" perspective.

Race differences in depression vulnerability following Hurricane Katrina.

OBJECTIVE: This study investigated whether racial disparities in depression were present after Hurricane Katrina. METHOD: Data were gathered from 932 New Orleans residents who were present when Hurricane Katrina struck, and who returned to New Orleans the following year. Multiple logistic regression models evaluated racial differences in screening positive for depression (a score ≥16 on the Center for Epidemiologic Studies Depression Scale), and explored whether differential vulnerability (prehurricane physical and mental health functioning and education level), differential exposure to hurricane-related stressors, and loss of social support moderated and/or reduced the association of race with depression. RESULTS: A univariate logistic regression analysis showed the odds for screening positive for depression were 86% higher for African Americans than for Caucasians (odds ratio [OR] = 1.86 [1.28-2.71], p = .0012). However, after controlling simultaneously for sociodemographic characteristics, preexisting vulnerabilities, social support, and trauma-specific factors, race was no longer a significant correlate for screening positive for depression (OR = 1.54 [0.95-2.48], p = .0771). CONCLUSIONS: The racial disparity in postdisaster depression seems to be confounded by sociodemographic characteristics, preexisting vulnerabilities, social support, and trauma-specific factors. Nonetheless, even after adjusting for these factors, there was a nonsignificant trend effect for race, which could suggest race played an important role in depression outcomes following Hurricane Katrina. Future studies should examine these associations prospectively, using stronger assessments for depression, and incorporate measures for discrimination and segregation, to further understand possible racial disparities in depression after Hurricane Katrina. (PsycINFO Database Record

MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance.

Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.

MYC degradation.

The MYC oncoprotein is an essential transcription factor that regulates the expression of many genes involved in cell growth, proliferation, and metabolic pathways. Thus, it is important to keep MYC activity in check in normal cells in order to avoid unwanted oncogenic changes. Normal cells have adapted several ways to control MYC levels, and these mechanisms can be disrupted in cancer cells. One of the major ways in which MYC levels are controlled in cells is through targeted degradation by the ubiquitin-proteasome system (UPS). Here, we discuss the role of the UPS in the regulation of MYC protein levels and review some of the many proteins that have been shown to regulate MYC protein stability. In addition, we discuss how this relates to MYC transcriptional activity, human cancers, and therapeutic targeting.

Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer.

UNLABELLED: Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and cancerous inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from patients with pancreatic cancer were sensitive to OP449 treatment, indicating that PP2A-regulated pathways are highly relevant to this deadly disease. IMPLICATIONS: The PP2A inhibitors SET and CIP2A are overexpressed in human pancreatic cancer and are important for pancreatic cancer cell growth and transformation; thus, antagonizing SET and/or CIP2A may be an innovative approach for the treatment of human pancreatic cancer.

Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis.

The Myc oncoprotein is considered a master regulator of gene transcription by virtue of its ability to modulate the expression of a large percentage of all genes. However, mechanisms that direct Myc's recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated Myc and its coactivators to select promoters during gene activation, followed by promoting Myc's release associated with its degradation. This facilitates Myc's activation of genes involved in cell growth and metabolism, resulting in enhanced proproliferative activity, even while controlling Myc levels. In cancer cells with impaired Myc degradation, Pin1 still enhances Myc DNA binding, although it no longer facilitates Myc degradation. Thus, we find that Pin1 and Myc are cooverexpressed in cancer, and this drives a gene expression pattern that we show is enriched in poor-outcome breast cancer subtypes. This study provides new insight into mechanisms regulating Myc DNA binding and oncogenic activity, it reveals a novel role for Pin1 in the regulation of transcription factors, and it elucidates a mechanism that can contribute to oncogenic cooperation between Pin1 and Myc.