The development of a successful radiation sensitivity predictive assay has been a major goal of radiation biology for several decades. We have developed a radiation classifier that predicts the inherent radiosensitivity of tumor cell lines as measured by survival fraction at 2 Gy (SF2), based on gene expression profiles obtained from the literature. Our classifier correctly predicts the SF2 value in 22 of 35 cell lines from the National Cancer Institute panel of 60, a result significantly different from chance (P = 0.0002). In our approach, we treat radiation sensitivity as a continuous variable, significance analysis of microarrays is used for gene selection, and a multivariate linear regression model is used for radiosensitivity prediction. The gene selection step identified three novel genes (RbAp48, RGS19, and R5PIA) of which expression values are correlated with radiation sensitivity. Gene expression was confirmed by quantitative real-time PCR. To biologically validate our classifier, we transfected RbAp48 into three cancer cell lines (HS-578T, MALME-3M, and MDA-MB-231). RbAp48 overexpression induced radiosensitization (1.5-to 2-fold) when compared with mock-transfected cell lines. Furthermore, we show that HS-578T-RbAp48 overexpressors have a higher proportion of cells in G 2 -M (27% versus 5%), the radiosensitive phase of the cell cycle. Finally, RbAp48 overexpression is correlated with dephosphorylation of Akt, suggesting that RbAp48 may be exerting its effect by antagonizing the Ras pathway. The implications of our findings are significant. We establish that radiation sensitivity can be predicted based on gene expression profiles and we introduce a genomic approach to the identification of novel molecular markers of radiation sensitivity. (Cancer Res 2005; 65(16): 7169-76)
PURPOSE-Historical data have indicated the potential for the histologically-normal breast to harbor pre-malignant changes at the molecular level. We postulated that a histologically-normal tissue with "tumor-like" gene expression pattern might harbor substantial risk for future cancer development. Genes associated with these high-risk tissues were considered to be "malignancy-risk genes".EXPERIMENTAL DESIGN-From a total of 90 breast cancer patients, we collected a set of 143 histologically-normal breast tissues derived from patients harboring breast cancer who underwent curative mastectomy, as well as a set of 42 invasive ductal carcinomas (IDC) of various histologic grades. All samples were assessed for global gene expression differences using microarray analysis. For the purpose of this study we defined normal breast tissue to include histologically normal and benign lesions.RESULTS-Here we report the discovery of a "malignancy-risk" gene signature that may portend risk of breast cancer development in benign, but molecularly-abnormal, breast tissue. Pathway analysis showed that the malignancy-risk signature had a dramatic enrichment for genes with proliferative function, but appears to be independent of ER, PR, and HER2 status. The signature was validated by RT-PCR, with a high correlation (Pearson correlation=0.95 with p<0.0001) with microarray data.CONCLUSION-These results suggest a predictive role for the malignancy-risk signature in normal breast tissue. Proliferative biology dominates the earliest stages of tumor development.While breast cancer therapy has seen substantial advances over the last few decades (1, 2 ), predicting breast cancer risk in the apparently normal breast is still problematic (3-9 ). AlthoughCorrespondence should be addressed to T.Y. (Timothy.Yeatman@moffitt.org).• Aejaz Nasir is a joining first author. NIH Public Access Author ManuscriptBreast Cancer Res Treat. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Breast Cancer Res Treat. 2010 January ; 119(2): 335-346. doi:10.1007/s10549-009-0344-y. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript a few pre-malignant histologic risk factors have been identified (atypical ductal hyperplasia (ADH), lobular carcinoma in situ, microcalcifications) (10, 11 ), few tools exist to distinguish the normal breast from the breast at risk for cancer (3-9 ). Furthermore, in patients who are treated for invasive breast cancer, the risk of local recurrence remains in spite of histologically negative margins. Wapnir et al (12) observed 10-year cumulative local recurrence rates ranging from 4.8% to 10.1% across five National Surgical Adjuvant Breast and Bowel Project (NSABP) trials involving 2,669 node-positive patients treated between 1984 and 1994, and 10-year local recurrence rates of 3.5% to 6.5% were observed in node-negative patients receiving systemic treatment in NSABP trials (13) during the same time period.Recent developments of gene signatures for breast cancer have been rep...
Tumor progression is a multistep process, which enables cells to evolve from benign to malignant tumors. This progression has been suggested to depend on six essential characteristics identified as the "hallmarks of cancer," which include: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Osteopontin (OPN) is an integrin-binding protein that has been shown to be associated with the progression of several cancer types, and to play an important functional role in various aspects of malignancy, particularly tissue invasion and metastasis. Here we studied genes regulated by OPN in a model of human breast cancer using oligonucleotide microarray technology by comparing the gene-expression profiles of 21NT mammary carcinoma cells transfected to overexpress OPN versus mock-transfected control cells. From over 12,000 human genes, we identified 99 known human genes differentially regulated by OPN whose expression changed by at least 1.5-fold and showed statistically significant differences in mean expression levels between groups. Functional classification of these genes into the hallmarks of cancer categories showed that OPN can affect the expression of genes involved in all six categories in this model. Furthermore, we were able to validate the expression of 18/19 selected candidate genes by quantitative real-time PCR, further supporting our microarray findings. This study provides the first evidence that OPN can lead to numerous gene expression changes that influence multiple aspects of tumor progression and malignant growth.
BackgroundThe epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer progression and may promote resistance to therapy. An analysis of patients (n = 71) profiled with both gene expression and a global microRNA assessment (∼415 miRs) identified miR-147 as highly anti-correlated with an EMT gene expression signature score and postulated to reverse EMT (MET).Methods and FindingsmiR-147 was transfected into colon cancer cells (HCT116, SW480) as well as lung cancer cells (A-549). The cells were assessed for morphological changes, and evaluated for effects on invasion, motility, and the expression of key EMT markers. Resistance to chemotherapy was evaluated by treating cells with gefitinib, an EGFR inhibitor. The downstream genes regulated by miR-147 were assayed using the Affymetrix GeneChip U133 Plus2.0 platform. miR-147 was identified to: 1. cause MET primarily by increasing the expression of CDH1 and decreasing that of ZEB1; 2. inhibit the invasion and motility of cells; 3. cause G1 arrest by up-regulating p27 and down-regulating cyclin D1. miR-147 also dramatically reversed the native drug resistance of the colon cancer cell line HCT116 to gefitinib. miR-147 significantly repressed Akt phosphorylation, and knockdown of Akt with siRNA induced MET. The morphologic effects of miR-147 on cells appear to be attenuated by TGF-B1, promoting a plastic and reversible transition between MET and EMT.ConclusionmiR-147 induced cancer cells to undergo MET and induced cell cycle arrest, suggesting a potential tumor suppressor role. miR-147 strikingly increased the sensitivity to EGFR inhibitor, gefitinib in cell with native resistance. We conclude that miR-147 might have therapeutic potential given its ability to inhibit proliferation, induce MET, as well as reverse drug sensitivity.
Osteopontin (OPN) is a secreted phosphoglycoprotein known to interact with a number of integrin receptors. While increased OPN expression has been reported in a number of human cancers, and its cognate receptors (alphav-beta3, alphav-beta5, and alphav-beta1 integrins and CD44) have been identified, its role in colon cancer development and progression has not been extensively studied. We previously identified, using a combination of gene expression and tissue microarrays, that increased OPN expression is concordant with tumor stage. The current study examined the functional role of OPN in colon cancer progression and metastatic potential. The principal findings of this study were that both endogenous OPN expression (via stable transfection) as well as exogenous OPN (added to culture medium) enhanced the motility and invasive capacity of human colon cancer cells in vitro. OPN appeared to regulate motility though interaction with CD44. OPN expression also reduced intercellular (homotypic) adhesion, an important characteristic of metastatic cancer cells. Stable transfection of four poorly tumorigenic human colon cancer cell lines with OPN also resulted in enhanced tumorigenicity in vivo with increased proliferation and increased CD31 positive microvessel counts, concordant with the degree of OPN expression. Collectively, these results suggest that OPN may affect multiple functional components contributing to human colon cancer progression and solidifies its role in this process.
We have identified a seven-miRNA signature that is associated with metastatic potential in the primary tumor. Forced overexpression of three downregulated miRNA resulted in attenuation of in vitro invasion, suggesting direct tumor suppressive function and further supporting the biological importance of complementary strand miRNA.
Clusterin is a widely expressed glycoprotein that has been paradoxically observed to have both pro-and antiapoptotic functions. Recent reports suggest this apparent dichotomy of function may be related to two different isoforms, one secreted and cytoplasmic, the other nuclear. To clarify the functional role of clusterin in regulating apoptosis, we examined its expression in human colon cancer tissues and in human colon cancer cell lines. We additionally explored its expression and activity using models of adenomatous polyposis coli (APC)-and chemotherapy-induced apoptosis. Clusterin RNA and protein levels were decreased in colon cancer tissues largely devoid of wild-type APC when compared with matched normal tissue controls, suggesting a means for invasive cancers to avoid apoptosis. Conversely, induction of apoptosis by expression of wildtype APC or by treatment with chemotherapy led to increased clusterin RNA and protein levels localizing to apoptotic nuclei. We found that transient transfection of clusterin to colon cancer cell lines directly enhanced basal and chemotherapy-induced apoptosis. Clusterin-induced apoptosis was inhibited by antisense clusterin and was found to be highly dependent on p21 but not p53 expression, yet a deficit in p21 can be subverted by clusterin transfection. Collectively, these data support the hypothesis that nuclear clusterin function is proapoptotic when induced by APC or chemotherapy in the context of p21 expression. Absent of p21, clusterin in not induced, and apoptosis is significantly inhibited. These data support a potential therapeutic role for clusterin in enhancing chemotherapy-induced apoptosis and in promoting apoptosis in cells deficient in p21.
Postdoctoral training for psychologists has increased. This article provides an overview of postdoctoral fellowships, including information regarding training opportunities and requirements for licensure and employment. A developmental perspective on the postdoctoral training experience is offered, focusing on negotiating the tasks of individuation and self-definition. Special attention is paid to personal issues. As the postdoctoral fellow's professional identity solidifies, he or she develops expertise in focused areas of interest, experiences a deepening commitment to the work, develops an increasing sense of self-efficacy and self-acceptance as a psychologist, and gains respect from others as a competent professional. This enables the postdoctoral fellow to develop more collegial relationships with former mentors, teachers, and supervisors and shift toward the practice of professional psychology and the teaching of more junior professionals.Postdoctoral clinical, counseling, and clinical research experiences have become popular and increasingly necessary for obtaining licensure and employment (Follette & Klesges, 1988). The most recent National Conference on Internship Training in Psychology (Belar, Bieliauskas, Larsen, & Mensh, 1987) recommended that internship training be 2 years in length, 1 year predoctoral and 1 year postdoctoral. As can be NADINE KASLOW received her PhD from the University of Houston in 1983. She is currently an associate professor in the Department of Psychiatry and the
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