The experience of living with metastatic breast cancer--a review of the literature.

Women's experiences with metastatic breast cancer have received little research attention. We reviewed published articles (1984-2013) reporting research examining women's experiences of metastatic breast cancer (n = 33). Findings from quantitative studies were categorized into three broad areas: adverse consequences, satisfaction with health care providers, and strategies for living. Themes identified from qualitative findings include living as a social outsider; importance of hope; health and quality of life; positive experiences; experiences at end of life; and strategies for living. More research is needed to explore experiences of subgroups to appropriately respond to women's diverse care needs.

Ets-1 regulates energy metabolism in cancer cells.

Cancer cells predominantly utilize glycolysis for ATP production even in the presence of abundant oxygen, an environment that would normally result in energy production through oxidative phosphorylation. Although the molecular mechanism for this metabolic switch to aerobic glycolysis has not been fully elucidated, it is likely that mitochondrial damage to the electron transport chain and the resulting increased production of reactive oxygen species are significant driving forces. In this study, we have investigated the role of the transcription factor Ets-1 in the regulation of mitochondrial function and metabolism. Ets-1 was over-expressed using a stably-incorporated tetracycline-inducible expression vector in the ovarian cancer cell line 2008, which does not express detectable basal levels of Ets-1 protein. Microarray analysis of the effects of Ets-1 over-expression in these ovarian cancer cells shows that Ets-1 up-regulates key enzymes involved in glycolysis and associated feeder pathways, fatty acid metabolism, and antioxidant defense. In contrast, Ets-1 down-regulates genes involved in the citric acid cycle, electron transport chain, and mitochondrial proteins. At the functional level, we have found that Ets-1 expression is directly correlated with cellular oxygen consumption whereby increased expression causes decreased oxygen consumption. Ets-1 over-expression also caused increased sensitivity to glycolytic inhibitors, as well as growth inhibition in a glucose-depleted culture environment. Collectively our findings demonstrate that Ets-1 is involved in the regulation of cellular metabolism and response to oxidative stress in ovarian cancer cells.

Mechanisms associated with mitochondrial-generated reactive oxygen species in cancer.

The mitochondria are unique cellular organelles that contain their own genome and, in conjunction with the nucleus, are able to transcribe and translate genes encoding components of the electron transport chain (ETC). To do so, the mitochondria must communicate with the nucleus via the production of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), which are produced as a byproduct of aerobic respiration within the mitochondria. Mitochondrial signaling is proposed to be altered in cancer cells, where the mitochondria are frequently found to harbor mutations within their genome and display altered functional characteristics leading to increased glycolysis. As signaling molecules, ROS oxidize and inhibit MAPK phosphatases resulting in enhanced proliferation and survival, an effect particularly advantageous to cancer cells. In terms of transcriptional regulation, ROS affect the phosphorylation, activation, oxidation, and DNA binding of transcription factors such as AP-1, NF-kappaB, p53, and HIF-1alpha, leading to changes in target gene expression. Increased ROS production by defective cancer cell mitochondria also results in the upregulation of the transcription factor Ets-1, a factor that has been increasingly associated with aggressive cancers.

Sleeping infants safely - considerations for GPs.

The sudden death of an infant is a traumatic experience for both families and health practitioners. The most common cause of sudden infant death is SIDS, defined as 'the sudden and unexpected death of an infant under 1 year of age, with onset of lethal episode apparently occurring during sleep, that remains unexplained after a thorough investigation including performance of a complete autopsy review of the circumstances of death and clinical history'. In 2004, SIDS accounted for 4.5% of deaths in infants aged less than 1 year in New South Wales. Evidence suggests the most common age of death from SIDS is 2-5 months, with a peak incidence at around 3-4 months.

Medication abortion in Canada: a right-to-health perspective.

The right to health under the International Covenant on Economic, Social, and Cultural Rights, to which Canada is a signatory, entitles women to available, accessible, and acceptable abortion care. Abortion care in Canada currently fails this standard. Medication abortion (the use of drugs to terminate a pregnancy) could improve abortion care in Canada, but its potential remains unrealized. This is in part attributable to the unavailability of mifepristone, the safest and most effective pharmaceutical for medication abortion. Given that it could improve abortion care, we investigated why mifepristone remains unapproved in Canada, whether its unavailability is attributable to government inaction, and whether Canada is therefore failing to fulfill its obligations under the right to health.

Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain.

BACKGROUND: Human retinoic acid teratogenesis results in malformations of dorsally derived hindbrain structures such as the cerebellum, noradrenergic hindbrain neurons and the precerebellar system. These structures originate from the rhombic lip and adjacent dorsal precursor pools that border the fourth ventricle roofplate. While retinoic acid synthesis is known to occur in the meninges that blanket the hindbrain, the particular sensitivity of only dorsal structures to disruptions in retinoid signalling is puzzling. We therefore looked for evidence within the neural tube for more spatiotemporally specific signalling pathways using an in situ hybridisation screen of known retinoic acid pathway transcripts. RESULTS: We find that there are highly restricted domains of retinoic acid synthesis and breakdown within specific hindbrain nuclei as well as the ventricular layer and roofplate. Intriguingly, transcripts of cellular retinoic acid binding protein 1 are always found at the interface between dividing and post-mitotic cells. By contrast to earlier stages of development, domains of synthesis and breakdown in post-mitotic neurons are co-localised. At the rhombic lip, expression of the mRNA for retinoic acid synthesising and catabolising enzymes is spatially highly organised with respect to the Cath1-positive precursors of migratory precerebellar neurons. CONCLUSION: The late developing hindbrain shows patterns of retinoic acid synthesis and use that are distinct from the well characterised phase of rostrocaudal patterning. Selected post-mitotic populations, such as the locus coeruleus, appear to both make and break down retinoic acid suggesting that a requirement for an autocrine, or at least a highly localised paracrine signalling network, might explain its acute sensitivity to retinoic acid disruption. At the rhombic lip, retinoic acid is likely to act as a dorsalising factor in parallel with other roofplate signalling pathways. While its precise role is unclear, retinoic acid is potentially well placed to regulate temporally determined cell fate decisions within the rhombic lip precursor pool.

RALDH-independent generation of retinoic acid during vertebrate embryogenesis by CYP1B1.

Several independent lines of evidence have revealed an instructive role for retinoic acid (RA) signalling in the establishment of normal pattern and cellular specification of the vertebrate embryo. Molecular analyses have previously identified the major RA-synthesising (RALDH1-3) and RA-degrading (CYP26A-C1) enzymes as well as other components involved in RA processing (e.g. CRABP). Although the majority of the early effects of RA can be attributed to the activity of RALDH2, many other effects are suggestive of the presence of an as yet unidentified RA source. Here we describe the identification, expression, biochemistry and functional analysis of CYP1B1, a member of the cytochrome p450 family of mono-oxygenases, and provide evidence that it contributes to RA synthesis during embryonic patterning. We present in vitro biochemical data demonstrating that this enzyme can generate both all-trans-retinal (t-RAL) and all-trans-retinoic acid (t-RA) from the precursor all-trans-retinol (t-ROH), but unlike the CYP26s, CYP1B1 cannot degrade t-RA. In particular, we focussed on the capacity of CYP1B1 to regulate the molecular mechanisms associated with dorsoventral patterning of the neural tube and acquisition of motor neuron progenitor domain identity. Concordant with its sites of expression and biochemistry, data are presented demonstrating that CYP1B1 is capable of eliciting responses that are consistent with the production of RA. Taken together, we propose that these data provide strong support for CYP1B1 being one of the RALDH-independent components by which embryos direct RA-mediated patterning.

VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail.

The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that the expression of a homophilic adhesion molecule, E-cadherin, a major constituent of epithelial cell junctions whose loss is associated with the progression of epithelial cancers, is significantly down-regulated in primary CC-RCC and CC-RCC cell lines devoid of VHL. Reintroduction of wild-type VHL in CC-RCC (VHL(-/-)) cells markedly reduced the expression of E2 box-dependent E-cadherin-specific transcriptional repressors Snail and SIP1 and concomitantly restored E-cadherin expression. RNA interference-mediated knockdown of HIFalpha in CC-RCC (VHL(-/-)) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants incapable of promoting HIFalpha degradation attenuated E-cadherin expression, correlating with the disengagement of RNA polymerase II from the endogenous E-cadherin promoter/gene. These findings reveal a critical HIF-dependent molecular pathway connecting VHL, an established "gatekeeper" of the renal epithelium, with a major epithelial tumor suppressor, E-cadherin.

ets-1 is transcriptionally up-regulated by H2O2 via an antioxidant response element.

Expression of the transcription factor Ets-1 is increasingly associated with the progression of several human cancers. A tumor-derived factor is expected to be involved in the inappropriate up-regulation of ets-1 in tumor and surrounding cells. A link between hydrogen peroxide (H2O2) and increased Ets-1 expression has also been suggested, leading to the proposal that this reactive oxygen species (ROS) may be an important factor in directly regulating the expression of ets-1 in tumor cells. Ets-1 expression in response to H2O2 was examined in an ovarian carcinoma cell model, and the genes promoter region was analyzed in order to identify putative elements involved in redox responsiveness. The up-regulation of Ets-1 by H2O2 was confirmed in the cells tested. Luciferase assays using constructs generated to test the contribution of specific promoter elements indicated that an antioxidant response element (ARE) is primarily involved in the H2O2-mediated induction. Gel shift analysis confirmed the increased binding of an Nrf2 containing protein complex to the ets-1 ARE after H2O2 treatment. This study has delineated a key element involved in the transcriptional regulation of ets-1 under basal and induced conditions. Ets-1 has obvious deleterious effects in many cancer cells, and thus, the identification of this regulatory pathway has provided possible targets for manipulating its expression.

Role of the transcription factor Ets-1 in cisplatin resistance.

Cisplatin is a DNA damaging agent widely used as a chemotherapeutic agent. A major limitation of the use of this agent is the development of drug resistance within tumors. Several in vitro models exist which enable the investigation of resistance mechanisms, including 2008/C13* ovarian carcinoma cells. C13* cells are variants of 2008 cells, displaying cisplatin resistance following 13 consecutive cisplatin treatments. This model system has led to the identification of several mechanisms that play parts in the multifactorial nature of cisplatin resistance. In this study, we have examined the contribution of a transcription factor, Ets-1, to the cisplatin resistance of C13* cells. Ets-1 is up-regulated in C13* cells as compared with the cisplatin-sensitive 2008 cells and overexpression of this protein in 2008 cells led to a 7-fold increase in resistance. Further studies on a colorectal carcinoma cell line overexpressing Ets-1 indicated that this phenomenon is not cell specific-increased cisplatin resistance correlated to Ets-1 expression. The mechanism of cisplatin resistance elicited by Ets-1 is potentially via transcriptional activation of genes whose products have well-described functions in reducing cisplatin toxicity. Examples, identified via microarray analysis, include metallothioneins and DNA repair enzymes. This is the first report to our knowledge associating expression of Ets-1, a transcription factor whose expression often signals poor prognosis in various cancer types, to cisplatin resistance.

Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is induced by genistein through the expression of p53 in colorectal cancer cells.

Genistein is an isoflavenoid found in soy that has anti-tumorigenic activities. Treatment of colorectal carcinoma HCT-116 cells with 50 microM genistein results in a 50% reduction in cell proliferation and a 6-fold increase in apoptosis. Genistein induces nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a protein with antitumorigenic activities, in a time- and concentration-dependent manner in HCT-116 cells. In addition, p53 and p21 are induced in HCT-116 cells. The induction of p53 (3 hr) precedes the induction of NAG-1 (12 hr), suggesting that genistein-induced NAG-1 expression is mediated by p53. In contrast, NAG-1 is not induced by genistein in the p53-negative colorectal carcinoma cell line HCT-15. Luciferase reporter constructs of the NAG-1 promoter containing 2 p53 sites showed that the p53 sites within the NAG-1 promoter are critical to genistein-induced NAG-1 expression in p53-positive U2OS cells. The expression of p53 was critical for NAG-1 promoter activity since no promoter activity was observed with genistein treatment in HCT-15 cells. However, genistein-induced promoter activity was restored in HCT-15 cells by transfection with wild-type p53. Together our data suggest a relationship between genistein, p53 and NAG-1 forming a novel pathway responsible for the antitumorigenic activity of genistein.

Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma ) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity.

Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand that has pro-apoptotic activity in human colon cancer. Although TGZ binds to PPAR gamma transcription factors as an agonist, emerging evidence suggests that TGZ acts independently of PPAR gamma in many functions, including apoptosis. Early growth response-1 (Egr-1) transcription factor has been linked to apoptosis and shown to be activated by extracellular signal-regulated kinase (ERK). We investigated whether TGZ-induced apoptosis may be related to Egr-1 induction, because TGZ has been known to induce ERK activity. Our results show that Egr-1 is induced dramatically by TGZ but not by other PPAR gamma ligands. TGZ affects Egr-1 induction at least by two mechanisms; TGZ increases Egr-1 promoter activity by 2-fold and prolongs Egr-1 mRNA stability by 3-fold. Inhibition of ERK phosphorylation in HCT-116 cells abolishes the Egr-1 induction by TGZ, suggesting its ERK-dependent manner. Further, the TGZ-induced Egr-1 expression results in increased promoter activity using a reporter system containing four copies of Egr-1 binding sites, and TGZ induces Egr-1 binding activity to Egr-1 consensus sites as assessed by gel shift assay. In addition, TGZ induces ERK-dependent phosphorylation of PPAR gamma, resulting in the down-regulation of PPAR gamma activity. The fact that TGZ-induced apoptosis is accompanied by the biosynthesis of Egr-1 suggests that Egr-1 plays a pivotal role in TGZ-induced apoptosis in HCT-116 cells. Our results suggest that Egr-1 induction is a unique property of TGZ compared with other PPAR gamma ligands and is independent of PPAR gamma activation. Thus, the up-regulation of Egr-1 may provide an explanation for the anti-tumorigenic properties of TGZ.

Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma.

Human prostate tumors have elevated levels of 15-lipoxygenase-1 (15-LOX-1) and data suggest that 15-LOX-1 may play a role in the development of prostate cancer. In contrast, 15-LOX-2 expression is higher in normal rather than in tumor prostate tissue and appears to suppress cancer development. We recently reported that 13-(S)-HODE, the 15-LOX-1 metabolite, up-regulates the MAP kinase signaling pathway and subsequently down-regulates PPARgamma in human colorectal carcinoma cells. To determine whether this mechanism is applicable to prostate cancer and what the effects of 15-LOX-2 are, we investigated the effect of 15-LOX-1, 15-LOX-2, and their metabolites on epidermal growth factor (EGF)- and insulin-like growth factor (IGF)-1 signaling in prostate carcinoma cells. In PC3 cells, 13-(S)-HODE, a 15-LOX-1 metabolite, up-regulated MAP kinase while in contrast 15-(S)-HETE, a 15-LOX-2 metabolite, down-regulated MAP kinase. As a result, 13-(S)-HODE increased PPARgamma phosphorylation while a subsequent decrease in PPARgamma phosphorylation was observed with 15-(S)-HETE. Thus, 15-LOX metabolites have opposing effects on the regulation of the MAP kinase signaling pathway and a downstream target of MAP kinase signaling like PPARgamma. In addition to the EGF signaling pathway, the IGF signaling pathway appears to be linked to prostate cancer. 13-(S)-HODE and 15-(S)-HETE up-regulate or down-regulate, respectively, both the MAPK and Akt pathways after activation with IGF-1. Thus, the effect of these lipid metabolites is not solely restricted to EGF signaling and not solely restricted to MAPK signaling. These results provide a plausible mechanism to explain the apparent opposing effects 15-LOX-1 and 15-LOX-2 play in prostate cancer.

Dual function of nonsteroidal anti-inflammatory drugs (NSAIDs): inhibition of cyclooxygenase and induction of NSAID-activated gene.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of inflammatory disease and have a chemopreventive effect on colorectal cancer. NSAIDs inhibit cyclooxygenase (COX)-1 and/or COX-2 activity, but the chemopreventive effect may be, in part, independent of prostaglandin inhibition. NSAID-activated gene (NAG-1) was previously identified as a gene induced by some NSAIDs in cells devoid of COX activity. NAG-1 has proapoptotic and antitumorigenic activity in vitro and in vivo. To determine whether the induction of NAG-1 by NSAIDs is influenced by COX expression, we developed COX-1- and COX-2-overexpressing HCT-116 cells. COX expression did not affect NSAID-induced NAG-1 expression as assessed by transient and stable transfection. Also, NAG-1 expression was not affected by PGE(2) and arachidonic acid, suggesting that NAG-1 induction by NSAIDs occurs by a prostanoid-independent manner. We also report that indomethacin increased NAG-1 expression in a number of cells from tissues other than colorectal. In conclusion, NSAIDs have dual function, induction of NAG-1 expression and inhibition of COX activity that occurs in a variety of cell lines.

Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53.

Dietary phenolic substances including resveratrol, a stillbene compound, are found in several fruits and vegetables, and these compounds have been reported to have anti-oxidant, anti-inflammatory and antitumorigenic activities. However, the molecular mechanisms underlying the antitumorigenic or chemopreventive activities of these compounds remain largely unknown. The expression of NAG-1 [non-steroidal anti-inflammatory (NSAID) drug-activated gene-1], a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be associated with pro-apoptotic and antitumorigenic activities. Here, we have demonstrated that resveratrol induces NAG-1 expression and apoptosis in a concentration-dependent manner. Resveratrol increases the expression of p53, tumor suppressor protein, prior to NAG-1 induction, indicating that NAG-1 expression by resveratrol is mediated by p53 expression. We also show that the p53 binding sites within the promoter region of NAG-1 play a pivotal role to control NAG-1 expression by resveratrol. Derivatives of resveratrol were examined for NAG-1 induction, and the data suggest that resveratrol-induced NAG-1 and p53 induction is not dependent on its anti-oxidant activity. The data may provide linkage between p53, NAG-1 and resveratrol, and in part, a new clue to the molecular mechanism of the antitumorigenic activity of natural polyphenolic compounds.