Gene Summary

Gene:CD36; CD36 molecule (thrombospondin receptor)
Summary:The protein encoded by this gene is the fourth major glycoprotein of the platelet surface and serves as a receptor for thrombospondin in platelets and various cell lines. Since thrombospondins are widely distributed proteins involved in a variety of adhesive processes, this protein may have important functions as a cell adhesion molecule. It binds to collagen, thrombospondin, anionic phospholipids and oxidized LDL. It directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and it binds long chain fatty acids and may function in the transport and/or as a regulator of fatty acid transport. Mutations in this gene cause platelet glycoprotein deficiency. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:platelet glycoprotein 4
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD36 (cancer-related)

Bockhorn J, Prat A, Chang YF, et al.
Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models.
Cancer Res. 2014; 74(24):7406-17 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)-derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met-derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial-mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype.

Wolf MJ, Adili A, Piotrowitz K, et al.
Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.
Cancer Cell. 2014; 26(4):549-64 [PubMed] Related Publications
Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8(+) T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8(+) T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8(+) and NKT cells cooperatively induce liver damage. Hepatocellular LTβR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.

Kataria Y, Wright M, Deaton RJ, et al.
Dietary influences on tissue concentrations of phytanic acid and AMACR expression in the benign human prostate.
Prostate. 2015; 75(2):200-10 [PubMed] Related Publications
BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR) is an enzyme involved in fatty acid metabolism that is markedly over-expressed in virtually all prostate cancers (PCa), relative to benign tissue. One of AMACR's primary substrates, phytanic acid, is derived predominately from red meat and dairy product consumption. Epidemiological evidence suggests links between dairy/red meat intake, as well as phytanic acid levels, and elevated PCa risk. This study investigates the relationships among dietary intake, serum and tissue concentrations of phytanic acid, and AMACR expression (mRNA and protein) in the histologically benign human prostate.
METHODS: Men undergoing radical prostatectomy for the treatment of localized disease provided a food frequency questionnaire (n = 68), fasting blood (n = 35), benign fresh frozen prostate tissue (n = 26), and formalin-fixed paraffin-embedded (FFPE) sections (n = 67). Serum and tissue phytanic acid concentrations were obtained by gas chromatography-mass spectrometry. We extracted RNA from epithelial cells using laser capture microdissection and quantified mRNA expression of AMACR and other genes involved in the peroxisomal phytanic acid metabolism pathway via qRT-PCR. Immunohistochemistry for AMACR was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between diet, serum, and tissue phytanic acid levels, as well as AMACR and other gene expression levels were assessed by partial Spearman correlation coefficients.
RESULTS: High-fat dairy intake was the strongest predictor of circulating phytanic acid concentrations (r = 0.35, P = 0.04). Tissue phytanic acid concentrations were not associated with any dietary sources and were only weakly correlated with serum levels (r = 0.29, P = 0.15). AMACR gene expression was not associated with serum phytanic acid (r = 0.13, P = 0.47), prostatic phytanic acid concentrations (r = 0.03, P = 0.88), or AMACR protein expression (r = -0.16, P = 0.20).
CONCLUSIONS: Our data underscore the complexity of the relationship between AMACR and its substrates and do not support the unifying hypothesis that excess levels of dietary phytanic acid are responsible for both the overexpression of AMACR in prostate cancer and the potential association between PCa risk and intake of dairy foods and red meat.

Kasiappan R, Sun Y, Lungchukiet P, et al.
Vitamin D suppresses leptin stimulation of cancer growth through microRNA.
Cancer Res. 2014; 74(21):6194-204 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Obesity is a pandemic and major risk factor for cancers. The reduction of obesity would have been an effective strategy for cancer prevention, but the reality is that worldwide obesity has kept increasing for decades, remaining a major avoidable cancer risk secondary only to smoke. The present studies suggest that vitamin D may be an effective agent to reduce obesity-associated cancer risks in women. Molecular analyses showed that leptin increased human telomerase reverse transcriptase (hTERT) mRNA expression and cell growth through estrogen receptor-α (ERα) activation in ovarian cancer cells, which was suppressed by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The suppression was compromised when miR-498 induction by the hormone was depleted with microRNA (miRNA) sponges. In mice, high-fat diet (HFD) stimulation of ovarian tumor growth was remarkably suppressed by 1,25(OH)2D3 analogue EB1089, which was also compromised by miR-498 sponges. EB1089 did not alter HFD-induced increase in serum leptin levels but increased miR-498 and decreased the diet-induced hTERT expression in tumors. Quantitative RT-PCR analyses revealed an inverse correlation between hTERT mRNA and miR-498 in response to 1,25(OH)2D3 in estrogen-sensitive ovarian, endometrial, and breast cancers. The studies suggest that miR-498-mediated hTERT downregulation is a key event mediating the anti-leptin activity of 1,25(OH)2D3 in estrogen-sensitive tumors in women.

Kuhbier JW, Bucan V, Reimers K, et al.
Observed changes in the morphology and phenotype of breast cancer cells in direct co-culture with adipose-derived stem cells.
Plast Reconstr Surg. 2014; 134(3):414-23 [PubMed] Related Publications
BACKGROUND: Regarding aesthetics and long-term stability, cell-assisted lipotransfer is a promising method for breast reconstruction. Here, autologous fat grafts enriched with autologous adipose-derived stem cells are transferred. However, as adipose-derived stem cells secrete high amounts of growth factors, potential risks of tumor reactivation remain. In this study, influences of adipose-derived stem cells on inflammatory breast cancer cells were evaluated in a direct co-culture system.
METHODS: Human adipose-derived stem cells were isolated and cultivated either alone or in a direct co-culture with the inflammatory breast carcinoma cell line T47D. At different time points, cell morphology was observed by scanning electron microscopy, cell membranes were stained by immunofluorescence, and gene expression was analyzed by real-time polymerase chain reaction.
RESULTS: In co-cultures, T47D breast carcinoma cells showed tumorsphere-typical growth surrounded by a monolayer of adipose-derived stem cells. Direct cell-to-cell contacts could be observed between the two different cell types. Immunofluorescence revealed vesicular exchange and fusion between carcinoma cells and adipose-derived stem cells. Expression levels of transcriptional genes for typical malignancy markers were substantially higher in co-cultures compared with single cultures.
CONCLUSIONS: Direct intercellular contact between carcinoma cells and adipose-derived stem cells by means of exosomal vesicular exchange was revealed. Breast cancer cells displayed a change towards a more malignant phenotype associated with higher rates of metastasis and worsened prognosis. As cell-assisted lipotransfer is often performed after breast cancer surgery, transfer of adipose-derived stem cells might lead to deterioration of prognosis in case of recurrence as it has been described for inflammatory breast cancer.

Thompson P, Wheeler HE, Delaney SM, et al.
Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children's Oncology Group.
Cancer Chemother Pharmacol. 2014; 74(4):831-8 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.
PATIENTS AND METHODS: Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95% for age or as body fat >30%. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters.
RESULTS: A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m(2)/h ± 14% and 68.1 L/m(2) ± 24%, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m(2)/h ± 5.6% and 232 L/m(2) ± 10%, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction.
CONCLUSIONS: We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.

Kim JJ, Choi YM, Hong MA, et al.
Gene dose effect between a fat mass and obesity-associated polymorphism and body mass index was observed in Korean women with polycystic ovary syndrome but not in control women.
Fertil Steril. 2014; 102(4):1143-1148.e2 [PubMed] Related Publications
OBJECTIVE: To examine the association between fat mass and obesity-associated (FTO) polymorphisms and polycystic ovary syndrome (PCOS) in Korean women.
DESIGN: Case-control study.
SETTING: University department of obstetrics and gynecology.
PATIENT(S): Women with (n = 552) or without (n = 559) PCOS.
INTERVENTION(S): Genotyping was performed.
MAIN OUTCOME MEASURE(S): FTO rs9939609 genotype distribution and correlation between variants in this gene and PCOS phenotypes.
RESULT(S): The mean body mass index (BMI) of the patients was significantly higher than that of the control subjects (22.0 ± 4.1 kg/m(2) vs. 20.1 ± 2.5 kg/m(2)), but most (81.3%) of the patients were not obese. FTO rs9939609 was not significantly associated with PCOS itself. However, a positive correlation was observed between the number of variant alleles and BMI in women with PCOS: Each additional copy of the variant allele increased BMI by a mean (95% confidence interval) of 4.8% (1.4%-8.3%) or 1.11 kg/m(2) (1.03-1.20 kg/m(2)) after adjusting for age. This correlation was not observed in the control subjects.
CONCLUSION(S): FTO rs9939609 was not a major determinant of PCOS. However, in the women with PCOS who were primarily nonobese, a gene dose effect was observed for BMI. The FTO gene may play an influential role in predisposition to PCOS via an association with obesity.

Chen L, Xu WM, Zhang D
Association of abdominal obesity, insulin resistance, and oxidative stress in adipose tissue in women with polycystic ovary syndrome.
Fertil Steril. 2014; 102(4):1167-1174.e4 [PubMed] Related Publications
OBJECTIVE: To study the expression of insulin signaling-related genes and oxidative stress markers in the visceral adipose tissue obtained from polycystic ovary syndrome (PCOS) patients and healthy control subjects and to investigate the relationships among abdominal obesity, insulin resistance, and oxidative stress at the tissue level.
DESIGN: Case-control study.
SETTING: University teaching hospital.
PATIENT(S): In total, 30 PCOS patients and 30 healthy control subjects, who underwent laparoscopic surgery, were included in the study.
INTERVENTION(S): Abdominal obesity was defined based on waist circumference (WC). The homeostasis model index was used to assess insulin resistance (HOMA-IR).
MAIN OUTCOME MEASURE(S): Gene expression of glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS1) in visceral adipose tissue (VAT) and the parameters of oxidative stress, such as superoxide dismutase, enzyme glutathione reductase, and dimethylarginine, were measured, and the expression of protein oxidative damage product 3-nitro-tyrosine residues (nitrotyrosine) in VAT was identified with the use of immunohistochemistry.
RESULT(S): PCOS was associated with lower expression of GLUT4 and IRS1 and a higher level of oxidative stress in VAT, which was strongly correlated with WC and HOMA-IR. Presence of abdominal obesity further intensified the correlations observed in our measurements. The nitrotyrosine expression in VAT was stronger in PCOS patients.
CONCLUSION(S): The strong correlation of insulin resistance with oxidative stress at the VAT level suggests that local oxidative stress and abnormalities of insulin signaling in adipose tissue play critical roles in the pathogenesis of PCOS.

Kir S, White JP, Kleiner S, et al.
Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia.
Nature. 2014; 513(7516):100-4 [PubMed] Article available free on PMC after 04/03/2015 Related Publications
Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

Li B, Qiu B, Lee DS, et al.
Fructose-1,6-bisphosphatase opposes renal carcinoma progression.
Nature. 2014; 513(7517):251-5 [PubMed] Article available free on PMC after 11/03/2015 Related Publications
Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.

Cerdá C, Sánchez C, Climent B, et al.
Oxidative stress and DNA damage in obesity-related tumorigenesis.
Adv Exp Med Biol. 2014; 824:5-17 [PubMed] Related Publications
Reactive oxygen species induce oxidative modification of critical macromolecules. Oxygen derived free radicals may act as potential cytotoxic intermediates inducing inflammatory and degenerative processes, or as signal messengers for the regulation of gene expression. This dual effect mainly depends on the availability of free radicals in terms of concentration, as well as on the environmental characteristics in which they are produced. The formation of free radicals has been proposed to be the linking factor between certain metabolic disturbances and cancer. Circulating mononuclear cells of patients with high cholesterol levels, insulin resistance, metabolic syndrome or obesity present lower levels of antioxidant enzymes and increased concentrations of oxidative stress by-products such as isoprostanes or the DNA oxidized and highly mutagenic base 8-oxo-7,8-dihydro-2'-deoxyguanosine. Overweight or obese subjects also exhibit hormonal changes as a consequence of the increase of mass fat, and these hormonal alterations have been implicated in the alteration of different signal transduction mechanisms and in cell growth and differentiation. A significant correlation has been found between body mass index and cancer. The biological factors and molecular mechanisms implicated in obesity associated cancer susceptibility will be reviewed.

Higurashi T, Endo H, Uchiyama T, et al.
Conditional knockout of the leptin receptor in the colonic epithelium revealed the local effects of leptin receptor signaling in the progression of colonic tumors in mice.
Carcinogenesis. 2014; 35(9):2134-41 [PubMed] Related Publications
Leptin, secreted by the adipose tissue and known to be related to obesity, is considered to be involved in the onset and progression of colorectal cancer. However, the exact role of leptin in colorectal carcinogenesis is still unclear, as several controversial reports have been published on the various systemic effects of leptin. The aim of this study was to clarify the local and precise roles of leptin receptor (LEPR)-mediated signaling in colonic carcinogenesis using intestinal epithelium-specific LEPRb conditional knockout (cKO) mice. We produced and used colonic epithelium-specific LEPRb cKO mice to investigate the carcinogen-induced formation of aberrant crypt foci (ACF) and tumors in the colon, using their littermates as control. There were no differences in the body weight or systemic condition between the control and cKO mice. The tumor sizes and number of large-sized tumors were significantly lower in the cKO mice as compared with those in the control mice. On the other hand, there was no significant difference in the proliferative activity of the normal colonic epithelial cells or ACF formation between the control and cKO mice. In the control mice, marked increase of the LEPRb expression level was observed in the colonic tumors as compared with that in the normal epithelium; furthermore, signal transducer and activator of transcription (STAT3) was activated in the tumor cells. These findings suggest that STAT3 is one of the important molecules downstream of LEPRb, and LEPRb/STAT3 signaling controls tumor cell proliferation. We demonstrated the importance of local/regional LEPR-mediated signaling in colorectal carcinogenesis.

Myles IA
Fast food fever: reviewing the impacts of the Western diet on immunity.
Nutr J. 2014; 13:61 [PubMed] Article available free on PMC after 11/03/2015 Related Publications
While numerous changes in human lifestyle constitute modern life, our diet has been gaining attention as a potential contributor to the increase in immune-mediated diseases. The Western diet is characterized by an over consumption and reduced variety of refined sugars, salt, and saturated fat. Herein our objective is to detail the mechanisms for the Western diet's impact on immune function. The manuscript reviews the impacts and mechanisms of harm for our over-indulgence in sugar, salt, and fat, as well as the data outlining the impacts of artificial sweeteners, gluten, and genetically modified foods; attention is given to revealing where the literature on the immune impacts of macronutrients is limited to either animal or in vitro models versus where human trials exist. Detailed attention is given to the dietary impact on the gut microbiome and the mechanisms by which our poor dietary choices are encoded into our gut, our genes, and are passed to our offspring. While today's modern diet may provide beneficial protection from micro- and macronutrient deficiencies, our over abundance of calories and the macronutrients that compose our diet may all lead to increased inflammation, reduced control of infection, increased rates of cancer, and increased risk for allergic and auto-inflammatory disease.

Wang T, Gilkes DM, Takano N, et al.
Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis.
Proc Natl Acad Sci U S A. 2014; 111(31):E3234-42 [PubMed] Article available free on PMC after 11/03/2015 Related Publications
Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.

Umemura A, Park EJ, Taniguchi K, et al.
Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition.
Cell Metab. 2014; 20(1):133-44 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuates liver inflammation and tumorigenesis. Notably, rapamycin treatment or hepatocyte-specific ablation of the specific mTORC1 subunit Raptor resulted in elevated interleukin-6 (IL-6) production, activation of signal transducer and activator of transcription 3 (STAT3), and enhanced HCC development, despite a transient reduction in hepatosteatosis. These results suggest that long-term rapamycin treatment, which also increases IL-6 production in humans, is unsuitable for prevention or treatment of obesity-promoted liver cancer.

Mu Z, Klinowska T, Dong X, et al.
AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), HER2, and HER3: preclinical activity in HER2 non-amplified inflammatory breast cancer models.
J Exp Clin Cancer Res. 2014; 33:47 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
INTRODUCTION: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC). Epidermal growth factor receptor 2 (HER2) overexpression is observed at a higher rate in IBC compared with noninflammatory breast cancer. Current clinically available anti-HER2 therapies are effective only in patients with HER2 amplified breast cancer, including IBC. AZD8931 is a novel small-molecule equipotent inhibitor of EGFR, HER2, and HER3 signaling. In this study, we investigated the antitumor activity of AZD8931 alone or in combination with paclitaxel using preclinical models of EGFR-overexpressed and HER2 non-amplified IBC cells.
METHODS: Two IBC cell lines SUM149 and FC-IBC-02 derived from pleural effusion of an IBC patient were used in this study. Cell growth and apoptotic cell death were examined in vitro. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice. AZD8931 was given by daily oral gavage at doses of 25 mg/kg, 5 days/week for 4 weeks. Paclitaxel was subcutaneously injected twice weekly.
RESULTS: AZD8931 significantly suppressed cell growth of IBC cells and induced apoptosis of human IBC cells in vitro. Significantly, we showed that AZD8931 monotherapy inhibited xenograft growth and the combination of paclitaxel + AZD8931 was demonstrably more effective than paclitaxel or AZD8931 alone treatment at delaying tumor growth in vivo in orthotopic IBC models.
CONCLUSION: AZD8931 single agent and in combination with paclitaxel demonstrated signal inhibition and antitumor activity in EGFR-overexpressed and HER2 non-amplified IBC models. These results suggest that AZD8931 may provide a novel therapeutic strategy for the treatment of IBC patients with HER2 non-amplified tumors.

Gauger KJ, Bassa LM, Henchey EM, et al.
The effects of diet induced obesity on breast cancer associated pathways in mice deficient in SFRP1.
Mol Cancer. 2014; 13:117 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Secreted frizzled-related proteins (SFRPs) are a family of proteins that block the Wnt signaling pathway and loss of Sfrp1 expression is observed in breast cancer. The molecular mechanisms by which obesity contributes to breast tumorigenesis are not well defined, but involve increased inflammation. Mice deficient in Sfrp1 show enhanced mammary gland inflammation in response to diet induced obesity (DIO). Furthermore, mammary glands from Sfrp1-/- mice exhibit increased Wnt signaling, decreased cell death responses, and excessive hyper branching. The work described here was initiated to investigate whether obesity exacerbates the aforementioned pathways, as they each play a key roles in the development of breast cancer.
FINDINGS: Wnt signaling is significantly affected by DIO and Sfrp1-/- loss as revealed by analysis of Myc mRNA expression and active β-catenin protein expression. Furthermore, Sfrp1-/- mice fed a high fat diet (HFD) exhibit an increase in mammary cell proliferation. The death response is also impaired in the mammary gland of Sfrp1-/- mice fed a normal diet (ND) as well as a HFD. In response to γ-irradiation, mammary glands from Sfrp1-/- mice express significantly less Bax and Bbc3 mRNA, caspase-3 positive cells, and p53 protein. The expression of Wnt4 and Tnfs11 are critical for normal progesterone mediated mammary gland development and in response to obesity, Sfrp1-/- mice express significantly more Wnt4 and Tnfs11 mRNA expression. Evaluation of progesterone receptor (PR) expression showed that DIO increases the number of PR positive cells.
CONCLUSIONS: Our data indicate that the expression of Sfrp1 is a critical factor required for maintaining appropriate cellular homeostasis in response to the onset of obesity.

Dagher J, Dugay F, Rioux-Leclercq N, et al.
Cytoplasmic PAR-3 protein expression is associated with adverse prognostic factors in clear cell renal cell carcinoma and independently impacts survival.
Hum Pathol. 2014; 45(8):1639-46 [PubMed] Related Publications
Clear cell renal cell carcinomas (ccRCCs) represent 70% of renal cancers, and several clinical and histolopathological factors are implicated in their prognosis. We recently demonstrated that the overexpression of PAR-3 protein encoded by the PARD3 gene could be implicated in renal oncogenesis. The object of this work was to study the association of intratumoral PAR-3 expression with known prognostic parameters and clinical outcome. In this aim, PAR-3 expression was assessed by immunohistochemistry in ccRCC tumors of 101 patients from 2003 to 2005. The immunostaining of PAR-3 was scored either as membranous (mPAR-3) or as both membranous and cytoplasmic (cPAR-3). Cytoplasmic PAR-3 was significantly associated with worse histopathological and clinical prognostic factors: Fuhrman grades 3 and 4, tumor necrosis, sarcomatoid component, adrenal invasion, renal and hilar fat invasion, eosinophilic component, a noninactivated VHL gene, higher tumor grade, lymph node involvement, metastasis, and worse clinical Eastern Cooperative Oncology Group and S classification scores. After multivariate analysis, 2 parameters were independently associated with cPAR-3: necrosis and eosinophilic components. In addition, cPAR-3 patients had shorter overall and progression-free survivals independently from strong prognostic validated factors like metastases. A cytoplasmic expression of PAR-3 is therefore implicated in worse clinical and pathological cancer features in ccRCC and could be useful to identify patients with high-risk tumors.

Montales MT, Melnyk SB, Simmen FA, Simmen RC
Maternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes.
Carcinogenesis. 2014; 35(9):2102-12 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-α and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk.

Xiao Y, Lin VY, Ke S, et al.
14-3-3τ promotes breast cancer invasion and metastasis by inhibiting RhoGDIα.
Mol Cell Biol. 2014; 34(14):2635-49 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
14-3-3τ is frequently overexpressed in breast cancer; however, whether it contributes to breast cancer progression remains undetermined. Here, we identify a critical role for 14-3-3τ in promoting breast cancer metastasis, in part through binding to and inhibition of RhoGDIα, a negative regulator of Rho GTPases and a metastasis suppressor. 14-3-3τ binds Ser174-phosphorylated RhoGDIα and blocks its association with Rho GTPases, thereby promoting epidermal growth factor (EGF)-induced RhoA, Rac1, and Cdc42 activation. When 14-3-3τ is overexpressed in MCF7 breast cancer cells that express 14-3-3τ at low levels, it increases motility, reduces adhesion, and promotes metastasis in mammary fat pad xenografts. On the other hand, depletion of 14-3-3τ in MCF7 cells and in an invasive cell line, MDA-MB231, inhibits Rho GTPase activation and blocks breast cancer migration and invasion. Moreover, 14-3-3τ overexpression in human breast tumors is associated with the activation of ROCK (a Rho GTPase effector), high metastatic rate, and shorter survival, underscoring a clinically significant role for 14-3-3τ in breast cancer progression. Our work indicates that 14-3-3τ is a novel therapeutic target to prevent breast cancer metastasis.

Chaturvedi P, Gilkes DM, Takano N, Semenza GL
Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment.
Proc Natl Acad Sci U S A. 2014; 111(20):E2120-9 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Intratumoral hypoxia induces the recruitment of stromal cells, such as macrophages and mesenchymal stem cells (MSCs), which stimulate invasion and metastasis by breast cancer cells (BCCs). Production of macrophage colony-stimulating factor 1 (CSF1) by BCCs is required for macrophage recruitment, but the mechanisms underlying CSF1 expression have not been delineated. Triple-negative breast cancers have increased expression of genes regulated by hypoxia-inducible factors (HIFs). In this study, we delineate two feed-forward signaling loops between human MDA-MB-231 triple-negative BCCs and human MSCs that drive stromal cell recruitment to primary breast tumors. The first loop, in which BCCs secrete chemokine (C-X-C motif) ligand 16 (CXCL16) that binds to C-X-C chemokine receptor type 6 (CXCR6) on MSCs and MSCs secrete chemokine CXCL10 that binds to receptor CXCR3 on BCCs, drives recruitment of MSCs. The second loop, in which MSCs secrete chemokine (C-C motif) ligand 5 that binds to C-C chemokine receptor type 5 on BCCs and BCCs secrete cytokine CSF1 that binds to the CSF1 receptor on MSCs, drives recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. These two signaling loops operate independent of each other, but both are dependent on the transcriptional activity of HIFs, with hypoxia serving as a pathophysiological signal that synergizes with chemokine signals from MSCs to trigger CSF1 gene transcription in triple-negative BCCs.

Bosch A, Panoutsopoulou K, Corominas JM, et al.
The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells.
Oncotarget. 2014; 5(8):2065-76 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
In early stages of metastasis malignant cells must acquire phenotypic changes to enhance their migratory behavior and their ability to breach the matrix surrounding tumors and blood vessel walls. Epigenetic regulation of gene expression allows the acquisition of these features that, once tumoral cells have escape from the primary tumor, can be reverted. Here we report that the expression of the Polycomb epigenetic repressor Ring1B is enhanced in tumoral cells that invade the stroma in human ductal breast carcinoma and its expression is coincident with that of Fak in these tumors. Ring1B knockdown in breast cancer cell lines revealed that Ring1B is required to sustain Fak expression in basal conditions as well as in Tgfβ-treated cells. Functionally, endogenous Ring1B is required for cell migration and invasion in vitro and for in vivo invasion of the mammary fat pad by tumoral cells. Finally we identify p63 as a target of Ring1B to regulate Fak expression: Ring1B depletion results in enhanced p63 expression, which in turns represses Fak expression. Importantly, Fak downregulation upon Ring1B depletion is dependent on p63 expression. Our findings provide new insights in the biology of the breast carcinoma and open new avenues for breast cancer prognosis and therapy.

Keller E, Chazenbalk GD, Aguilera P, et al.
Impaired preadipocyte differentiation into adipocytes in subcutaneous abdominal adipose of PCOS-like female rhesus monkeys.
Endocrinology. 2014; 155(7):2696-703 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Metabolic characteristics of polycystic ovary syndrome women and polycystic ovary syndrome-like, prenatally androgenized (PA) female monkeys worsen with age, with altered adipogenesis of sc abdominal adipose potentially contributing to age-related adverse effects on metabolism. This study examines whether adipocyte morphology and gene expression in sc abdominal adipose differ between late reproductive-aged PA female rhesus monkeys compared with age-matched controls (C). Subcutaneous abdominal adipose of both groups was obtained for histological imaging and mRNA determination of zinc finger protein 423 (Zfp423) as a marker of adipose stem cell commitment to preadipocytes, and CCAAT/enhancer binding protein (C/EBP)α/peroxisome proliferator-activated receptor (PPAR)δ as well as C/EBPα/PPARγ as respective markers of early- and late-stage differentiation of preadipocytes to adipocytes. In all females combined, serum testosterone (T) levels positively correlated with fasting serum levels of total free fatty acid (r(2) = 0.73, P < .002). PA females had a greater population of small adipocytes vs C (P < .001) in the presence of increased Zfp423 (P < .025 vs C females) and decreased C/EBPα (P < .003, vs C females) mRNA expression. Moreover, Zfp423 mRNA expression positively correlated with circulating total free fatty acid levels during iv glucose tolerance testing (P < .004, r(2) = 0.66), whereas C/EBPα mRNA expression negatively correlated with serum T levels (P < .02, r(2) = 0.43). Gene expression of PPARδ and PPARγ were comparable between groups (P = .723 and P = .18, respectively). Early-to-mid gestational T excess in female rhesus monkeys impairs adult preadipocyte differentiation to adipocytes in sc abdominal adipose and may constrain the ability of this adipose depot to safely store fat with age.

Loganathan J, Jiang J, Smith A, et al.
The mushroom Ganoderma lucidum suppresses breast-to-lung cancer metastasis through the inhibition of pro-invasive genes.
Int J Oncol. 2014; 44(6):2009-15 [PubMed] Related Publications
Breast cancer metastasis is one of the major reasons for the high morbidity and mortality of breast cancer patients. In spite of surgical interventions, chemotherapy, radiation therapy and targeted therapy, some patients are considering alternative therapies with herbal/natural products. In the present study, we evaluated a well-characterized extract from the medicinal mushroom Ganoderma lucidum (GLE) for its affects on tumor growth and breast-to-lung cancer metastasis. MDA-MB-231 human breast cancer cells were implanted into the mammary fat pads of nude mice. GLE (100 mg/kg/every other day) was administered to the mice by an oral gavage for 4 weeks, and tumor size was measured using microcalipers. Lung metastases were evaluated by hematoxylin and eosin (H&E) staining. Gene expression in MDA-MB-231 cells was determined by DNA microarray analysis and confirmed by quantitative PCR. Identified genes were silenced by siRNA, and cell migration was determined in Boyden chambers and by wound-healing assay. Although an oral administration of GLE only slightly suppressed the growth of large tumors, the same treatment significantly inhibited the number of breast-to-lung cancer metastases. GLE also downregulated the expression of genes associated with invasive behavior (HRAS, VIL2, S100A4, MCAM, I2PP2A and FN1) in MDA-MB-231 cells. Gene silencing of HRAS, VIL2, S100A4, I2PP2A and FN1 by siRNA suppressed migration of MDA-MB‑231 cells. Our study suggests that an oral administration of GLE can inhibit breast-to-lung cancer metastases through the downregulation of genes responsible for cell invasiveness. The anti-metastatic benefits of GLE warrant further clinical studies.

Zhao T, Sun Q, del Rincon SV, et al.
Gallotannin imposes S phase arrest in breast cancer cells and suppresses the growth of triple-negative tumors in vivo.
PLoS One. 2014; 9(3):e92853 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Triple-negative breast cancers are associated with poor clinical outcomes and new therapeutic strategies are clearly needed. Gallotannin (Gltn) has been previously demonstrated to have potent anti-tumor properties against cholangiocarcinoma in mice, but little is known regarding its capacity to suppress tumor outgrowth in breast cancer models. We tested Gltn for potential growth inhibitory properties against a variety of breast cancer cell lines in vitro. In particular, triple-negative breast cancer cells display higher levels of sensitivity to Gltn. The loss of proliferative capacity in Gltn exposed cells is associated with slowed cell cycle progression and S phase arrest, dependent on Chk2 phosphorylation and further characterized by changes to proliferation related genes, such as cyclin D1 (CcnD1) as determined by Nanostring technology. Importantly, Gltn administered orally or via intraperitoneal (IP) injections greatly reduced tumor outgrowth of triple-negative breast cells from mammary fat pads without signs of toxicity. In conclusion, these data strongly suggest that Gltn represents a novel approach to treat triple-negative breast carcinomas.

Dowman JK, Hopkins LJ, Reynolds GM, et al.
Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle.
Am J Pathol. 2014; 184(5):1550-61 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.

Jami MS, Hou J, Liu M, et al.
Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness.
BMC Cancer. 2014; 14:194 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness.
METHODS: We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer.
RESULTS: KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility.
CONCLUSIONS: Our findings indicate that KIAA1199 may play an important role in breast tumor growth and invasiveness, and that it may represent a novel target for biomarker development and a novel therapeutic target for breast cancer.

Zhao X, Yang Y, Sun BF, et al.
FTO and obesity: mechanisms of association.
Curr Diab Rep. 2014; 14(5):486 [PubMed] Related Publications
The Fat mass and obesity associated (FTO) gene is a newly identified genetic factor for obesity. However, the exact molecular mechanisms responsible for the effect of FTO on obesity remain largely unknown. Recent studies from genome-wide associated studies reveal that genetic variants in the FTO gene are associated not only with human adiposity and metabolic disorders, but also with cancer, a highly obesity-associated disease as well. Data from animal and cellular models further demonstrate that the perturbation of FTO enzymatic activity dysregulates genes related to energy metabolism, causing the malfunction of energy and adipose tissue homeostasis in mice. The most significant advance about FTO research is the recent discovery of FTO as the first N6-methyl-adenosine (m(6)A) RNA demethylase that catalyzes the m(6)A demethylation in α-ketoglutarate - and Fe(2+)-dependent manners. This finding provides the strong evidence that the dynamic and reversible chemical m(6)A modification on RNA may act as a novel epitranscriptomic marker. Furthermore, the FTO protein was observed to be partially localized onto nuclear speckles enriching mRNA processing factors, implying a potential role of FTO in regulating RNA processing. This review summarizes the recent progress about biological functions of FTO through disease-association studies as well as the data from in vitro and in vivo models, and highlights the biochemical features of FTO that might be linked to obesity.

Leibovich-Rivkin T, Liubomirski Y, Meshel T, et al.
The inflammatory cytokine TNFα cooperates with Ras in elevating metastasis and turns WT-Ras to a tumor-promoting entity in MCF-7 cells.
BMC Cancer. 2014; 14:158 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: In the present study we determined the relative contribution of two processes to breast cancer progression: (1) Intrinsic events, such as activation of the Ras pathway and down-regulation of p53; (2) The inflammatory cytokines TNFα and IL-1β, shown in our published studies to be highly expressed in tumors of >80% of breast cancer patients with recurrent disease.
METHODS: Using MCF-7 human breast tumor cells originally expressing WT-Ras and WT-p53, we determined the impact of the above-mentioned elements and cooperativity between them on the expression of CXCL8 (ELISA, qRT-PCR), a member of a "cancer-related chemokine cluster" that we have previously identified. Then, we determined the mechanisms involved (Ras-binding-domain assays, Western blot, luciferase), and tested the impact of Ras + TNFα on angiogenicity (chorioallantoic membrane assays) and on tumor growth at the mammary fat pad of mice and on metastasis, in vivo.
RESULTS: Using RasG12V that recapitulates multiple stimulations induced by receptor tyrosine kinases, we found that RasG12V alone induced CXCL8 expression at the mRNA and protein levels, whereas down-regulation of p53 did not. TNFα and IL-1β potently induced CXCL8 expression and synergized with RasG12V, together leading to amplified CXCL8 expression. Testing the impact of WT-Ras, which is the common form in breast cancer patients, we found that WT-Ras was not active in promoting CXCL8; however, TNFα has induced the activation of WT-Ras: joining these two elements has led to cooperative induction of CXCL8 expression, via the activation of MEK, NF-κB and AP-1. Importantly, TNFα has led to increased expression of WT-Ras in an active GTP-bound form, with properties similar to those of RasG12V. Jointly, TNFα + Ras activities have given rise to increased angiogenesis and to elevated tumor cell dissemination to lymph nodes.
CONCLUSIONS: TNFα cooperates with Ras in promoting the metastatic phenotype of MCF-7 breast tumor cells, and turns WT-Ras into a tumor-supporting entity. Thus, in breast cancer patients the cytokine may rescue the pro-cancerous potential of WT-Ras, and together these two elements may lead to a more aggressive disease. These findings have clinical relevance, suggesting that we need to consider new therapeutic regimens that inhibit Ras and TNFα, in breast cancer patients.

Taguchi A, Kawana K, Tomio K, et al.
Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo.
PLoS One. 2014; 9(2):e89605 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Cancer associated fibroblasts (CAFs) are responsible for tumor growth, angiogenesis, invasion, and metastasis. Matrix metalloproteinase (MMP)-9 secreted from cancer stroma populated by CAFs is a prerequisite for cancer angiogenesis and metastasis. Omega-3 polyunsaturated fatty acids (omega-3 PUFA) have been reported to have anti-tumor effects on diverse types of malignancies. Fat-1 mice, which can convert omega-6 to omega-3 PUFA independent of diet, are useful to investigate the functions of endogenous omega-3 PUFA. To examine the effect of omega-3 PUFA on tumorigenesis, TC-1 cells, a murine epithelial cell line immortalized by human papillomavirus (HPV) oncogenes, were injected subcutaneously into fat-1 or wild type mice. Tumor growth and angiogenesis of the TC-1 tumor were significantly suppressed in fat-1 compared to wild type mice. cDNA microarray of the tumors derived from fat-1 and wild type mice revealed that MMP-9 is downregulated in fat-1 mice. Immunohistochemical study demonstrated immunoreactivity for MMP-9 in the tumor stromal fibroblasts was diffusely positive in wild type whereas focal in fat-1 mice. MMP-9 was expressed in primary cultured fibroblasts isolated from fat-1 and wild type mice but was not expressed in TC-1 cells. Co-culture of fibroblasts with TC-1 cells enhanced the expression and the proteinase activity of MMP-9, although the protease activity of MMP-9 in fat-1-derived fibroblasts was lower than that in wild type fibroblasts. Our data suggests that omega-3 PUFAs suppress MMP-9 induction and tumor angiogenesis. These findings may provide insight into mechanisms by which omega-3 PUFAs exert anti-tumor effects by modulating tumor microenvironment.

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