Leonardo Salmena

Publications (37)607.85 Total impact

• Article: The functions and regulation of the PTEN tumour suppressor.

  Min Sup Song, Leonardo Salmena, Pier Paolo Pandolfi
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  ABSTRACT: The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer. By suppressing the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein-protein interactions, are all altered in cancer. The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus. Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies.
  Nature Reviews Molecular Cell Biology 04/2012; 13(5):283-96. · 39.12 Impact Factor
• Article: Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

  Joanne Kotsopoulos, Jan Lubinski, Leonardo Salmena, Henry T Lynch, Charmaine Kim-Sing, William D Foulkes, Parviz Ghadirian, Susan L Neuhausen, Rochelle Demsky, Nadine Tung, [......], Leigha Senter, Andrea Eisen, Charis Eng, Christian Singer, Ophira Ginsburg, Joanne Blum, Tomasz Huzarski, Aletta Poll, Ping Sun, Steven A Narod
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  ABSTRACT: INTRODUCTION: Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers. METHODS: We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer. RESULTS: Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43). CONCLUSIONS: These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.
  Breast cancer research: BCR 03/2012; 14(2):R42. · 5.24 Impact Factor
• Article: BRCA1 haploinsufficiency: consequences for breast cancer.

  Leonardo Salmena, Steven Narod
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  ABSTRACT: In their study, Konishi et al. generate and study cell lines that carry one mutant and one normal copy of BRCA1. These heterozygous (noncancerous) cells are noteworthy in that they carry an increased number of copy number alterations and have diminished DNA repair capacity. These observations go beyond the classical two-hit hypothesis for inherited cancers, whereby the cell phenotype is normal until the second allele is lost through somatic mutation or epigenetic silencing. They propose that BRCA1 heterozygosity is associated with increased genomic instability, which accelerates the mutation rate of other critical genes, including the second copy of BRCA1. They conclude that BRCA1 is a haploinsufficient tumor suppressor gene, which when lost through inheritance, increases a cell's susceptibility to acquire further mutations.
  Women s Health 03/2012; 8(2):127-9.
• Article: From photomorphogenesis to cancer: A CSN journey.

  Leonardo Salmena, Razqallah Hakem
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  ABSTRACT: Comment on: Chen B, et al. Cell Cycle 2012; 11:4633-41.
  Cell cycle (Georgetown, Tex.) 01/2012; 12(2). · 5.36 Impact Factor
• Article: BRCA1 and BRCA2 mutations and breast cancer.

  Steven A Narod, Leonardo Salmena
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  ABSTRACT: Genetic testing for BRCA mutations is expanding in clinical oncology centers worldwide. Testing may help target unaffected high-risk women for prevention and/or close surveillance and may also help affected women choose the best chemotherapy. Annual screening with MRI appears to be an effective surveillance strategy and should be added to mammographic screening. It is important to have an understanding of the pathologic features and the natural history of BRCA-associated breast cancers in order that individualized treatments can be developed and delivered. The goals of treatment for a woman with a BRCA-associated breast cancer should be to prevent recurrence of the initial cancer and to prevent second primary breast and ovarian cancers. Women with breast cancer and a BRCA1 mutation may benefit from tailored treatments, such as with cis-platinum or olaparib. Mutations in BRCA1 are distributed in populations throughout the world and it is important that the benefits of genetic testing and of targeted therapies be made available to women who live outside of North America and western Europe.
  Discovery medicine 11/2011; 12(66):445-53.
• Source

  Available from: Samuel Benchimol

  Article: Role of Pirh2 in mediating the regulation of p53 and c-Myc.

  Anne Hakem, Miyuki Bohgaki, Bénédicte Lemmers, Elisabeth Tai, Leonardo Salmena, Elzbieta Matysiak-Zablocki, Yong-Sam Jung, Jana Karaskova, Lilia Kaustov, Shili Duan, [......], Bayardo Perez-Ordonez, Anne-Marie Mes-Masson, Linda Penn, Jeremy Squire, Xinbin Chen, Igor Jurisica, Cheryl Arrowsmith, Otto Sanchez, Samuel Benchimol, Razqallah Hakem
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  ABSTRACT: Ubiquitylation is fundamental for the regulation of the stability and function of p53 and c-Myc. The E3 ligase Pirh2 has been reported to polyubiquitylate p53 and to mediate its proteasomal degradation. Here, using Pirh2 deficient mice, we report that Pirh2 is important for the in vivo regulation of p53 stability in response to DNA damage. We also demonstrate that c-Myc is a novel interacting protein for Pirh2 and that Pirh2 mediates its polyubiquitylation and proteolysis. Pirh2 mutant mice display elevated levels of c-Myc and are predisposed for plasma cell hyperplasia and tumorigenesis. Consistent with the role p53 plays in suppressing c-Myc-induced oncogenesis, its deficiency exacerbates tumorigenesis of Pirh2(-/-) mice. We also report that low expression of human PIRH2 in lung, ovarian, and breast cancers correlates with decreased patients' survival. Collectively, our data reveal the in vivo roles of Pirh2 in the regulation of p53 and c-Myc stability and support its role as a tumor suppressor.
  PLoS Genetics 11/2011; 7(11):e1002360. · 8.69 Impact Factor
• Source

  Available from: PubMed Central

  Article: Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice.

  Toshiyuki Bohgaki, Julien Mozo, Leonardo Salmena, Elzbieta Matysiak-Zablocki, Miyuki Bohgaki, Otto Sanchez, Andreas Strasser, Anne Hakem, Razqallah Hakem
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  ABSTRACT: Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim(-/-) mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim(-/-) T cells and restrains autoimmunity in Bim(-/-) mice.
  The Journal of Cell Biology 10/2011; 195(2):277-91. · 10.26 Impact Factor
• Source

  Available from: Florian Karreth

  Article: Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs.

  Yvonne Tay, Lev Kats, Leonardo Salmena, Dror Weiss, Shen Mynn Tan, Ugo Ala, Florian Karreth, Laura Poliseno, Paolo Provero, Ferdinando Di Cunto, Judy Lieberman, Isidore Rigoutsos, Pier Paolo Pandolfi
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  ABSTRACT: Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs.
  Cell 10/2011; 147(2):344-57. · 32.40 Impact Factor
• Article: A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?

  Leonardo Salmena, Laura Poliseno, Yvonne Tay, Lev Kats, Pier Paolo Pandolfi
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  ABSTRACT: Here, we present a unifying hypothesis about how messenger RNAs, transcribed pseudogenes, and long noncoding RNAs "talk" to each other using microRNA response elements (MREs) as letters of a new language. We propose that this "competing endogenous RNA" (ceRNA) activity forms a large-scale regulatory network across the transcriptome, greatly expanding the functional genetic information in the human genome and playing important roles in pathological conditions, such as cancer.
  Cell 08/2011; 146(3):353-8. · 32.40 Impact Factor
• Source

  Available from: Marcos Malumbres

  Article: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.

  Min Sup Song, Arkaitz Carracedo, Leonardo Salmena, Su Jung Song, Ainara Egia, Marcos Malumbres, Pier Paolo Pandolfi
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  ABSTRACT: PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies. PAPERCLIP:
  Cell 01/2011; 144(2):187-99. · 32.40 Impact Factor
• Article: A Role for PML in Innate Immunity.

  Andrea Lunardi, Mirella Gaboli, Marco Giorgio, Roberta Rivi, Anne Bygrave, Michael Antoniou, Dubravka Drabek, Elaine Dzierzak, Marta Fagioli, Leonardo Salmena, Marina Botto, Carlos Cordon-Cardo, Lucio Luzzatto, Pier Giuseppe Pelicci, Frank Grosveld, Pier Paolo Pandolfi
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  ABSTRACT: The promyelocytic leukemia gene (PML) of acute promyelocytic leukemia is an established tumor suppressor gene with critical functions in growth suppression, induction of apoptosis, and cellular senescence. Interestingly, although less studied, PML seems to play a key role also in immune response to viral infection. Herein, we report that Pml(-/-) mice spontaneously develop an atypical invasive and lethal granulomatous lesion known as botryomycosis (BTM). In Pml(-/-) mice, BTM is the result of impaired function of macrophages, whereby they fail to become activated and are thus unable to clear pathogenic microorganisms. Accordingly, Pml(-/-) mice are resistant to lipopolysaccharide (LPS)-induced septic shock as a result of an ineffective production of cytokines and chemokines, suggesting a role for PML in the innate immune Toll-like receptor (TLR)/NF-κB prosurvival pathway. These results not only shed light on a new fundamental function of PML in innate immunity, but they also point to a proto-oncogenic role for PML in certain cellular and pathological contexts.
  Genes & cancer 01/2011; 2(1):10-9.
• Source

  Available from: Stanislaw (Stan) Krajewski

  Article: Neuronal deletion of caspase 8 protects against brain injury in mouse models of controlled cortical impact and kainic acid-induced excitotoxicity.

  Maryla Krajewska, Zerong You, Juan Rong, Christina Kress, Xianshu Huang, Jinsheng Yang, Tiffany Kyoda, Ricardo Leyva, Steven Banares, Yue Hu, Chia-Hung Sze, Michael J Whalen, Leonardo Salmena, Razqallah Hakem, Brian P Head, John C Reed, Stan Krajewski
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  ABSTRACT: Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8(-/-)), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system. Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8(-/-) mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging. Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma.
  PLoS ONE 01/2011; 6(9):e24341. · 4.09 Impact Factor
• Article: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.

  Laura Poliseno, Leonardo Salmena, Jiangwen Zhang, Brett Carver, William J Haveman, Pier Paolo Pandolfi
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  ABSTRACT: The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.
  Nature 06/2010; 465(7301):1033-8. · 36.28 Impact Factor
• Article: Subtle variations in Pten dose determine cancer susceptibility.

  Andrea Alimonti, Arkaitz Carracedo, John G Clohessy, Lloyd C Trotman, Caterina Nardella, Ainara Egia, Leonardo Salmena, Katia Sampieri, William J Haveman, Edi Brogi, Andrea L Richardson, Jiangwen Zhang, Pier Paolo Pandolfi
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  ABSTRACT: Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. However, this hypothesis has not yet been definitively supported in vivo. Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes. Here we analyze Pten hypermorphic mice (Pten(hy/+)), expressing 80% normal levels of Pten. Pten(hy/+) mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosity. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner.
  Nature Genetics 05/2010; 42(5):454-8. · 35.53 Impact Factor
• Article: Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.

  Laura Poliseno, Leonardo Salmena, Luisa Riccardi, Alessandro Fornari, Min Sup Song, Robin M Hobbs, Paolo Sportoletti, Shorheh Varmeh, Ainara Egia, Giuseppe Fedele, Lucia Rameh, Massimo Loda, Pier Paolo Pandolfi
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  ABSTRACT: PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor that antagonizes signaling through the phosphatidylinositol 3-kinase-Akt pathway. We have demonstrated that subtle decreases in PTEN abundance can have critical consequences for tumorigenesis. Here, we used a computational approach to identify miR-22, miR-25, and miR-302 as three PTEN-targeting microRNA (miRNA) families found within nine genomic loci. We showed that miR-22 and the miR-106b~25 cluster are aberrantly overexpressed in human prostate cancer, correlate with abundance of the miRNA processing enzyme DICER, and potentiate cellular transformation both in vitro and in vivo. We demonstrated that the intronic miR-106b~25 cluster cooperates with its host gene MCM7 in cellular transformation both in vitro and in vivo, so that the concomitant overexpression of MCM7 and the miRNA cluster triggers prostatic intraepithelial neoplasia in transgenic mice. Therefore, the MCM7 gene locus delivers two simultaneous oncogenic insults when amplified or overexpressed in human cancer. Thus, we have uncovered a proto-oncogenic miRNA-dependent network for PTEN regulation and defined the MCM7 locus as a critical factor in initiating prostate tumorigenesis.
  Science Signaling 01/2010; 3(117):ra29. · 7.50 Impact Factor
• Article: Faithfull modeling of PTEN loss driven diseases in the mouse.

  Caterina Nardella, Arkaitz Carracedo, Leonardo Salmena, Pier Paolo Pandolfi
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  ABSTRACT: A decade of work has indisputably defined PTEN as a pivotal player in human health and disease. Above all, PTEN has been identified as one of the most commonly lost or mutated tumor suppressor genes in human cancers. For this reason, the generation of a multitude of mouse models has been an invaluable strategy to dissect the function and consequences-of-loss of this essential, evolutionary conserved lipid phosphatase in tumor initiation and progression.In this chapter, we will summarize the mouse models that have allowed us to faithfully recapitulate features of human cancers and to highlight the network of connections between the PTEN signaling cascade and other oncogenic or tumor suppressive pathways.Notably, PTEN represents one of the most extensively modeled genes involved in human cancer and exemplifies the strength of genetic mouse modeling as an approach to gain information aimed to improve our understanding of and ability to alleviate human disease.
  Current topics in microbiology and immunology 01/2010; 347:135-68. · 4.93 Impact Factor
• Article: Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling.

  Christina Gewinner, Zhigang C Wang, Andrea Richardson, Julie Teruya-Feldstein, Dariush Etemadmoghadam, David Bowtell, Jordi Barretina, William M Lin, Lucia Rameh, Leonardo Salmena, Pier Paolo Pandolfi, Lewis C Cantley
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  ABSTRACT: We report that knocking down the expression of inositol polyphosphate 4-phosphatase type II (INPP4B) in human epithelial cells, like knockdown of PTEN, resulted in enhanced Akt activation and anchorage-independent growth and enhanced overall motility. In xenograft experiments, overexpression of INPP4B resulted in reduced tumor growth. INPP4B preferentially hydrolyzes phosphatidylinositol-3,4-bisphosphate (PI(3,4)P(2)) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P(3)), suggesting that PI(3,4)P(2) and PI(3,4,5)P(3) may cooperate in Akt activation and cell transformation. Dual knockdown of INPP4B and PTEN resulted in cellular senescence. Finally, we found loss of heterozygosity (LOH) at the INPP4B locus in a majority of basal-like breast cancers, as well as in a significant fraction of ovarian cancers, which correlated with lower overall patient survival, suggesting that INPP4B is a tumor suppressor.
  Cancer cell 09/2009; 16(2):115-25. · 25.29 Impact Factor
• Article: High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia.

  Alejandro Gutierrez, Takaomi Sanda, Ruta Grebliunaite, Arkaitz Carracedo, Leonardo Salmena, Yebin Ahn, Suzanne Dahlberg, Donna Neuberg, Lisa A Moreau, Stuart S Winter, Richard Larson, Jianhua Zhang, Alexei Protopopov, Lynda Chin, Pier Paolo Pandolfi, Lewis B Silverman, Stephen P Hunger, Stephen E Sallan, A Thomas Look
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  ABSTRACT: To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.
  Blood 06/2009; 114(3):647-50. · 9.90 Impact Factor
• Article: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.

  Arkaitz Carracedo, Li Ma, Julie Teruya-Feldstein, Federico Rojo, Leonardo Salmena, Andrea Alimonti, Ainara Egia, Atsuo T Sasaki, George Thomas, Sara C Kozma, Antonella Papa, Caterina Nardella, Lewis C Cantley, Jose Baselga, Pier Paolo Pandolfi
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  ABSTRACT: Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.
  Journal of Clinical Investigation 10/2008; 118(9):3065-74. · 15.39 Impact Factor
• Article: Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.

  Caterina Nardella, Zhenbang Chen, Leonardo Salmena, Arkaitz Carracedo, Andrea Alimonti, Ainara Egia, Brett Carver, William Gerald, Carlos Cordon-Cardo, Pier Paolo Pandolfi
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  ABSTRACT: The mammalian target of rapamycin (mTOR) represents a critical signaling crossroad where pathways commonly disrupted in cancer converge. We report here that Rheb GTPase, the upstream activator of the mTOR complex 1 (mTORC1) is amplified in human prostate cancers. We demonstrate that Rheb overexpression promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate while eliciting a concomitant senescence response and a negative feedback loop limiting Akt activation. Importantly, we show that Pten haploinsufficiency cooperates with Rheb overexpression to markedly promote prostate tumorigenesis. We conclude that Rheb acts as a proto-oncogene in the appropriate genetic milieu and signaling context.
  Genes & Development 09/2008; 22(16):2172-7. · 11.66 Impact Factor