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Rostoker R.,Clinical Research Institute at Rambam CRIR | Rostoker R.,Technion - Israel Institute of Technology | Jayaprakash A.D.,Girihlet Inc. | LeRoith D.,Endocrinology
Genomics Data | Year: 2015

CD24 is an anchored cell surface marker that is highly expressed in cancer cells (Lee et al., 2009) and its expression is associated with poorer outcome of cancer patients (Kristiansen et al., 2003). Phenotype comparison between two subpopulations derived from the Mvt1 cell line, CD24- cells (with no CD24 cell surface expression) and the CD24+ cells, identified high tumorigenic capacity for the CD24+ cells. In order to reveal the transcripts that support the CD24+ aggressive and invasive phenotype we compared the gene profiles of these two subpopulations. mRNA profiles of CD24- and CD24+ cells were generated by deep sequencing, in triplicate, using an Illumina HiSeq 2500. Here we provide a detailed description of the mRNA-seq analysis from our recent study (Rostoker et al., 2015). The mRNA-seq data have been deposited in the NCBI GEO database (accession number GSE68746). © 2015 The Author. Source


Alikhani N.,Mount Sinai School of Medicine | Ferguson R.D.,Mount Sinai School of Medicine | Novosyadlyy R.,Mount Sinai School of Medicine | Gallagher E.J.,Mount Sinai School of Medicine | And 4 more authors.
Oncogene | Year: 2013

Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE -/-), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE -/- and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE -/- mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE -/- mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE -/- mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased AktS473 phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated AktS473 phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE -/- mice is a favorable setting for mammary tumor growth and metastasis. © 2013 Macmillan Publishers Limited All rights reserved. Source


Rostoker R.,Clinical Research Institute at Rambam CRIR | Ben-Shmuel S.,Clinical Research Institute at Rambam CRIR | Rashed R.,Clinical Research Institute at Rambam CRIR | Rashed R.,Technion - Israel Institute of Technology | And 3 more authors.
Breast Cancer Research | Year: 2016

Background: The pro-tumorigenic effects of the insulin-like growth factor receptor (IGF1R) are well described. IGF1R promotes cancer cell survival and proliferation and prevents apoptosis, and, additionally it was shown that IGF1R levels are significantly elevated in most common human malignancies including breast cancer. However, results from phase 3 clinical trials in unselected patients demonstrated lack of efficacy for anti-IGF1R therapy. These findings suggest that predictive biomarkers are greatly warranted in order to identify patients that will benefit from anti-IGF1R therapeutic strategies. Methods: Using the delivery of shRNA vectors into the Mvt1 cell line, we tested the role of the IGF1R in the development of mammary tumors. Based on CD24 cell surface expression, control and IGF1R-knockdown (IGF1R-KD) cells were FACS sorted into CD24- and CD24+ subsets and further characterized in vitro. The tumorigenic capacity of each was determined following orthotopic inoculation into the mammary fat pad of female mice. Tumor cells were FACS characterized upon sacrifice to determine IGF1R effect on the plasticity of this cell's phenotype. Metastatic capacity of the cells was assessed using the tail vein assay. Results: In this study we demonstrate that downregulation of the IGF1R specifically in cancer cells expressing CD24 on the cell surface membrane affect both their morphology (from mesenchymal-like into epithelial-like morphology) and phenotype in vitro. Moreover, we demonstrate that IGF1R-KD abolished both CD24+ cells capacity to form mammary tumors and lung metastatic lesions. We found in both cells and tumors a marked upregulation in CTFG and a significant reduction of SLP1 expression in the CD24+/IGF1R-KD; tumor-suppressor and tumor-promoting genes respectively. Moreover, we demonstrate here that the IGF1R is essential for the maintenance of stem/progenitor-like cancer cells and we further demonstrate that IGF1R-KD induces in vivo differentiation of the CD24+ cells toward the CD24- phenotype. This further supports the antitumorigenic effects of IGF1R-KD, as we recently published that these differentiated cells demonstrate significantly lower tumorigenic capacity compared with their CD24+ counterparts. Conclusions: Taken together these findings suggest that CD24 cell surface expression may serve as a valuable biomarker in order to identify mammary tumors that will positively respond to targeted IGF1R therapies. © 2016 Rostoker et al. Source


Scheinman E.J.,Technion - Israel Institute of Technology | Damouni R.,Technion - Israel Institute of Technology | Caspi A.,Clinical Research Institute at Rambam CRIR | Shen-Orr Z.,Clinical Research Institute at Rambam CRIR | And 4 more authors.
Diabetes/Metabolism Research and Reviews | Year: 2015

Background: Type 1 diabetes is an autoimmune disease, characterized by a loss of pancreatic β-cell mass and function, which results in dramatic reductions in insulin secretion and circulating insulin levels. Patients with type 1 diabetes are traditionally treated with insulin injections and insulin pumps ex vivo or undergo transplantation. Growth hormone (GH) has been shown to be involved in β-cell function and survival in culture. Methods: Twelve-week-old female C57BL/6 mice were treated with streptozotocin and monitored for their weight and blood glucose levels. Fourteen days post-initial injection, these mice were separated into two groups at random. One group was treated with GH while the other treated with vehicle for up to 3 weeks. These mice were compared with mice not treated with streptozotocin. Results: Under our experimental conditions, we observed that mice treated with GH had larger islets and higher serum insulin levels than streptozotocin-treated mice treated with saline (0.288 vs. 0.073 ng/mL, p<0.01). Conclusions: Our data demonstrate that GH may rescue islets and therefore may possess therapeutic potential in the treatment of type 1 diabetes, although consideration should be made regarding GH's effect on insulin resistance. © 2014 John Wiley & Sons, Ltd. Source


Ferguson R.D.,Mount Sinai School of Medicine | Gallagher E.J.,Mount Sinai School of Medicine | Scheinman E.J.,Clinical Research Institute at Rambam CRIR | Damouni R.,Clinical Research Institute at Rambam CRIR | And 2 more authors.
Vitamins and Hormones | Year: 2013

The worldwide epidemic of obesity is associated with increasing rates of the metabolic syndrome and type 2 diabetes. Epidemiological studies have reported that these conditions are linked to increased rates of cancer incidence and mortality. Obesity, particularly abdominal obesity, is associated with insulin resistance and the development of dyslipidemia, hyperglycemia, and ultimately type 2 diabetes. Although many metabolic abnormalities occur with obesity and type 2 diabetes, insulin resistance and hyperinsulinemia appear to be central to these conditions and may contribute to dyslipidemia and altered levels of circulating estrogens and androgens. In this review, we will discuss the epidemiological and molecular links between obesity, type 2 diabetes, and cancer, and how hyperinsulinemia and dyslipidemia may contribute to cancer development. We will discuss how these metabolic abnormalities may interact with estrogen signaling in breast cancer growth. Finally, we will discuss the effects of type 2 diabetes medications on cancer risk. © 2013 Elsevier Inc. Source

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