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Article ; Online: Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs

Hatice U. Osmanbeyoglu / Eneda Toska / Carmen Chan / José Baselga / Christina S. Leslie

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 14

Abstract: Cancer genomic data sets contain a wealth of data that can be used to predict prognosis and further understand disease. Here, the authors integrate multiple genomics data types to identify transcriptional dysregulation in response to somatic mutations. ...

Abstract	Cancer genomic data sets contain a wealth of data that can be used to predict prognosis and further understand disease. Here, the authors integrate multiple genomics data types to identify transcriptional dysregulation in response to somatic mutations.
Keywords	Science ; Q
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium

Joaquim Grego-Bessa / Joshua Bloomekatz / Pau Castel / Tatiana Omelchenko / José Baselga / Kathryn V Anderson

eLife, Vol

2016 Volume 5

Abstract: Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the ... ...

Abstract	Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the transition to a columnar epithelium fails in mutant embryos that lack the tumor suppressor PTEN, although proliferation, patterning and apical-basal polarity markers are normal in the mutants. The Pten phenotype is mimicked by constitutive activation of PI3 kinase and is rescued by the removal of PDK1 (PDPK1), but does not depend on the downstream kinases AKT and mTORC1. High resolution imaging shows that PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. The data suggest that appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis.
Keywords	epithelial morphogenesis ; neural tube defect ; tumor suppressor ; PI3 kinase ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction

Sherene Loi / Stefan Michiels / Jose Baselga / John M S Bartlett / Sandeep K Singhal / Vicky S Sabine / Andrew H Sims / Tarek Sahmoud / J Michael Dixon / Martine J Piccart / Christos Sotiriou

PLoS ONE, Vol 14, Iss 4, p e

PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer.

2019 Volume 0216175

Abstract: This corrects the article DOI:10.1371/journal.pone.0053292.]. ...

Abstract	[This corrects the article DOI:10.1371/journal.pone.0053292.].
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

Eneda Toska / Pau Castel / Sagar Chhangawala / Amaia Arruabarrena-Aristorena / Carmen Chan / Vasilis C. Hristidis / Emiliano Cocco / Mirna Sallaku / Guotai Xu / Jane Park / Gerard Minuesa / Sophie G. Shifman / Nicholas D. Socci / Richard Koche / Christina S. Leslie / Maurizio Scaltriti / José Baselga

Cell Reports, Vol 27, Iss 1, Pp 294-306.e

2019 Volume 5

Abstract: Summary: The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent ... ...

Abstract	Summary: The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Kα inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output. : Toska, Castel, et al. show that the PI3K pathway propagates its effects to control chromatin and estrogen receptor (ER) function through SGK1, a PI3K effector. PI3K inhibitors, via a negative-feedback loop, activate SGK1, which phosphorylates the histone lysine methyltransferase KMT2D to attenuate its activity and regulate ER response. Keywords: SGK1, KMT2D, PI3K pathway, estrogen receptor, breast cancer, chromatin regulation, AKT, PI3K inhibitors
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy

International Journal of Molecular Sciences, Vol 21, Iss 4, p

2020 Volume 1386

Abstract: Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after ... ...

Abstract	Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) ( p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%−68%), and 44% (95%CI 22%−69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23−9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%−81%) and 0% (95%CI 0%−31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.
Keywords	circulating micrornas ; biomarkers ; her2 ; breast cancer ; trastuzumab ; ct-mir-148a-3p ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma

Aviram Mizrachi / Yosi Shamay / Janki Shah / Samuel Brook / Joanne Soong / Vinagolu K. Rajasekhar / John L. Humm / John H. Healey / Simon N. Powell / José Baselga / Daniel A. Heller / Adriana Haimovitz-Friedman / Maurizio Scaltriti

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 10

Abstract: Head and neck squamous cell carcinomas (HNSCC) often harbourPIK3CAmutations but PI3Kα inhibitors can cause some side effects. Here, the authors develop P-selectin targeted nanoparticles to enhance tumour-specific delivery of a PI3Kα inhibitor to HNSCC ... ...

Abstract	Head and neck squamous cell carcinomas (HNSCC) often harbourPIK3CAmutations but PI3Kα inhibitors can cause some side effects. Here, the authors develop P-selectin targeted nanoparticles to enhance tumour-specific delivery of a PI3Kα inhibitor to HNSCC PDX and orthotopic xenograft models.
Keywords	Science ; Q
Language	English
Publishing date	2017-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Analysis and variability of TGFβ measurements in cancer patients with skeletal metastases

Peter J O’Brien / Rajeev Ramanathan / Jonathan M Yingling / Jose Baselga / Mace L Rothenberg

Biologics: Targets & Therapy, Vol 2008, Iss Issue 3, Pp 563-

2008 Volume 569

Abstract: Peter J O’Brien1, Rajeev Ramanathan2, Jonathan M Yingling1, Jose Baselga3, Mace L Rothenberg4, Michael Carducci5, Thomas Daly1, Dorothy Adcock2, Michael Lahn11Eli Lilly and Company Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA; ... ...

Abstract	Peter J O’Brien1, Rajeev Ramanathan2, Jonathan M Yingling1, Jose Baselga3, Mace L Rothenberg4, Michael Carducci5, Thomas Daly1, Dorothy Adcock2, Michael Lahn11Eli Lilly and Company Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA; 2Esoterix Coagulation, Aurora, CO, USA; 3Vall d’Hebron University Hospital, Barcelona, Spain; 4Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA; 5The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USAAbstract: Transforming growth factor beta (TGFβ) plays an important role in cancer, but accurate measurement of circulating TGFβ is complicated by the high TGFβ content of platelets which can release TGFβ ex vivo. We evaluated the use of citrate-theophylline-adenosine-dipyridamole (CTAD) tubes to reduce preanalytical variation in TGFβ measurements caused by ex vivo platelet activation. CTAD substantially reduced ex vivo platelet activation relative to traditional plasma collections in normal donors, which correlated with a decrease in measured TGFβ levels. We show that TGFβ levels are elevated in the majority of cancer patients with skeletal metastases, and that within-patient variability of these levels is relatively low over several weeks. Patients with elevated TGFβ could be subdivided into groups with or without evidence of platelet contribution to measured TGFβ levels. The use of CTAD tubes allows a better determination of a patient’s TGFβ status, and may improve classification of patients with oncologic disease.Keywords: TGFβ, cancer, biomarker, CTAD
Keywords	Medicine (General) ; R5-920
Language	English
Publishing date	2008-09-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer.

Sherene Loi / Stefan Michiels / Jose Baselga / John M S Bartlett / Sandeep K Singhal / Vicky S Sabine / Andrew H Sims / Tarek Sahmoud / J Michael Dixon / Martine J Piccart / Christos Sotiriou

PLoS ONE, Vol 8, Iss 1, p e

2013 Volume 53292

Abstract: The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR ... ...

Abstract	The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = -0.43, p = 0.008) compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R = -0.11, p = 0.37) but with relative change in phosphorlyated S6 (S240) (R = -0.46, p = 0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

Bruna, Alejandra / OscarÂ M. Rueda / Wendy Greenwood / AnkitaÂ Sati Batra / Maurizio Callari / RajbirÂ Nath Batra / Katherine Pogrebniak / Jose Sandoval / JohnÂ W. Cassidy / Ana Tufegdzic-Vidakovic / Stephen-John Sammut / Linda Jones / Elena Provenzano / Richard Baird / Peter Eirew / James Hadfield / Matthew Eldridge / Anne McLaren-Douglas / Andrew Barthorpe /

Howard Lightfoot / MarkÂ J. OâConnor / Joe Gray / Javier Cortes / Jose Baselga / Elisabetta Marangoni / AlanaÂ L. Welm / Samuel Aparicio / Violeta Serra / MathewÂ J. Garnett / Carlos Caldas

Cell. 2016 Sept. 22, v. 167

2016

Abstract: The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular ... ...

Abstract	The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining inÂ vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several exÂ vivo responses inÂ vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.
Keywords	biomarkers ; breast neoplasms ; drugs ; explants ; mice ; models ; neoplasm cells
Language	English
Dates of publication	2016-0922
Size	p. 260-274.e22.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2016.08.041
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Marta Castroviejo‐Bermejo / Cristina Cruz / Alba Llop‐Guevara / Sara Gutiérrez‐Enríquez / Mandy Ducy / Yasir Hussein Ibrahim / Albert Gris‐Oliver / Benedetta Pellegrino / Alejandra Bruna / Marta Guzmán / Olga Rodríguez / Judit Grueso / Sandra Bonache / Alejandro Moles‐Fernández / Guillermo Villacampa / Cristina Viaplana / Patricia Gómez / Maria Vidal / Vicente Peg /

EMBO Molecular Medicine, Vol 10, Iss 12, Pp n/a-n/a (2018)

2018

Abstract: Abstract Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend ... ...

Abstract	Abstract Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.
Keywords	BRCA1 ; homologous recombination ; PALB2 ; PARP inhibitors ; RAD51 ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	616
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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