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TP53 and triple negative breast cancer

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https://www.readbyqxmd.com/read/29719590/2-hydroxyflavanone-effectively-targets-rlip76-mediated-drug-transport-and-regulates-critical-signaling-networks-in-breast-cancer
#1
Lokesh Dalasanur Nagaprashantha, Jyotsana Singhal, Hongzhi Li, Charles Warden, Xueli Liu, David Horne, Sanjay Awasthi, Ravi Salgia, Sharad S Singhal
Breast cancer (BC) is the most common cancer in women. Estrogen, epidermal growth factor receptor 2 (ERBB2, HER2), and oxidative stress represent critical mechanistic nodes associated with BC. RLIP76 is a major mercapturic acid pathway transporter whose expression is increased in BC. In the quest of a novel molecule with chemopreventive and chemotherapeutic potential, we evaluated the effects of 2'-Hydroxyflavanone (2HF) in BC. 2HF enhanced the inhibitory effects of RLIP76 depletion and also inhibited RLIP76-mediated doxorubicin transport in BC cells...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29617654/identification-of-cdc25-as-a-common-therapeutic-target-for-triple-negative-breast-cancer
#2
Jeff C Liu, Letizia Granieri, Mariusz Shrestha, Dong-Yu Wang, Ioulia Vorobieva, Elizabeth A Rubie, Rob Jones, YoungJun Ju, Giovanna Pellecchia, Zhe Jiang, Carlo A Palmerini, Yaacov Ben-David, Sean E Egan, James R Woodgett, Gary D Bader, Alessandro Datti, Eldad Zacksenhaus
CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29616097/prognostic-significance-of-cd117-expression-and-tp53-missense-mutations-in-triple-negative-breast-cancer
#3
Yanli Luo, Wentao Huang, Huizhen Zhang, Guang Liu
Triple-negative breast cancer (TNBC) is extremely aggressive and associated with poor prognosis. There are no known predictive or prognostic markers for TNBC. Inhibition of tumor protein P53 ( TP53 ) has been demonstrated to increase the levels of cluster of differentiation 117 (CD117) in human colorectal cancer cells. However, the function of TP53 in the regulation of CD117 in TNBC has, to the best of our knowledge, not been reported. In the present study, the association between the expression of CD117 protein and TP53 mutations was investigated, and their prognostic value in patients with TNBC was assessed...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29564741/mutant-p53-in-breast-cancer-potential-as-a-therapeutic-target-and-biomarker
#4
REVIEW
Michael J Duffy, Naoise C Synnott, John Crown
OBJECTIVE: The aim of this article is to discuss mutant p53 as a possible therapeutic target and biomarker for breast cancer. RESULTS: TP53 (p53) is the most frequently mutated gene in invasive breast cancer. Although mutated in 30-35% of all cases, p53 is mutated in approximately 80% of triple-negative (TN) tumors (i.e., tumors negative for ER, PR, and HER2). Because of this high prevalence, mutated p53 is both a potential biomarker and therapeutic target for patients with breast cancer, especially for those with the TN subtype...
March 21, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29522266/gene-panel-testing-of-5589-brca1-2-negative-index-patients-with-breast-cancer-in-a-routine-diagnostic-setting-results-of-the-german-consortium-for-hereditary-breast-and-ovarian-cancer
#5
Jan Hauke, Judit Horvath, Eva Groß, Andrea Gehrig, Ellen Honisch, Karl Hackmann, Gunnar Schmidt, Norbert Arnold, Ulrike Faust, Christian Sutter, Julia Hentschel, Shan Wang-Gohrke, Mateja Smogavec, Bernhard H F Weber, Nana Weber-Lassalle, Konstantin Weber-Lassalle, Julika Borde, Corinna Ernst, Janine Altmüller, Alexander E Volk, Holger Thiele, Verena Hübbel, Peter Nürnberg, Katharina Keupp, Beatrix Versmold, Esther Pohl, Christian Kubisch, Sabine Grill, Victoria Paul, Natalie Herold, Nadine Lichey, Kerstin Rhiem, Nina Ditsch, Christian Ruckert, Barbara Wappenschmidt, Bernd Auber, Andreas Rump, Dieter Niederacher, Thomas Haaf, Juliane Ramser, Bernd Dworniczak, Christoph Engel, Alfons Meindl, Rita K Schmutzler, Eric Hahnen
The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing...
April 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29468485/characterization-of-a-novel-breast-cancer-cell-line-derived-from-a-metastatic-bone-lesion-of-a-breast-cancer-patient
#6
Julie Johnson, Darrell C Bessette, Jodi M Saunus, Chanel E Smart, Sarah Song, Rebecca L Johnston, Sibylle Cocciardi, Esdy N Rozali, Cameron N Johnstone, Ana Christina Vargas, Stephen H Kazakoff, Victorian Cancer BioBank, Kum Kum Khanna, Sunil R Lakhani, Georgia Chenevix-Trench, Peter T Simpson, Katia Nones, Nicola Waddell, Fares Al-Ejeh
PURPOSE: We aimed to generate and characterize a novel cell line from a breast cancer bone metastasis to better study the progression of the disease. METHODS: The cell line, P7731, was derived from a metastatic bone lesion of a breast cancer patient and assessed for marker expression. P7731 was analyzed for DNA copy number variation, somatic mutations, and gene expression and was compared with the primary tumor. RESULTS: P7731 cells are negative for estrogen receptor alpha (ERα), progesterone receptor (PR), and HER2 (triple-negative); strongly express vimentin (100% of cells positive) and also express cytokeratins 8/18 and 19 but at lower frequencies...
February 21, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29367998/identification-of-a-rhodium-iii-complex-as-a-wee1-inhibitor-against-tp53-mutated-triple-negative-breast-cancer-cells
#7
Guan-Jun Yang, Hai-Jing Zhong, Chung-Nga Ko, Suk-Yu Wong, Kasipandi Vellaisamy, Min Ye, Dik-Lung Ma, Chung-Hang Leung
The rhodium(iii) complex 1 was identified as a potent Wee1 inhibitor in vitro and in cellulo. It decreased Wee1 activity and unscheduled mitotic entry, and induced cell damage and death in TP53-mutated triple-negative breast cancer cells. 1 represents a promising scaffold for further development of more potent metal-based Wee1 antagonists.
January 25, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29365031/unravelling-triple-negative-breast-cancer-molecular-heterogeneity-using-an-integrative-multiomic-analysis
#8
Y Bareche, D Venet, M Ignatiadis, P Aftimos, M Piccart, F Rothe, C Sotiriou
Background: Recent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple negative breast cancers (TNBCs) reporting, at least 6 different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy...
January 22, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29203461/identifying-and-targeting-sporadic-oncogenic-genetic-aberrations-in-mouse-models-of-triple-negative-breast-cancer
#9
Hui Liu, Charles J Murphy, Florian A Karreth, Kristina B Emdal, Forest M White, Olivier Elemento, Alex Toker, Gerburg M Wulf, Lewis C Cantley
Triple-negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1 Amplifications or translocations that resulted in elevated oncoprotein expression or oncoprotein-containing fusions, respectively, as well as frameshift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated...
March 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29202330/genetic-alterations-in-sporadic-triple-negative-breast-cancer
#10
Laura-Ancuta Pop, Roxana-Maria Cojocneanu-Petric, Valentina Pileczki, Gabriela Morar-Bolba, Alexandru Irimie, Vladimir Lazar, Claudio Lombardo, Angelo Paradiso, Ioana Berindan-Neagoe
BACKGROUND: Recent studies have aimed to identify gene mutation profiles to explain the cause of TNBC therapy limitations. METHODS: The purpose of our study was to use Next Generation Sequencing (NGS) of 46 genes with a well-defined role in cancer in a cohort of TNBC patients in order to identify novel markers that could lead to the development of strategic, adjuvant, gene-targeted therapies. RESULTS: A total of 118 gene mutations in 35 genes, 75 mutations in BRCA1 and 92 mutations in BRCA2 were identified...
April 2018: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/29156674/novel-combinations-of-pi3k-mtor-inhibitors-with-dacomitinib-or-chemotherapy-in-pten-deficient-patient-derived-tumor-xenografts
#11
Irene Brana, Nhu-An Pham, Lucia Kim, Shingo Sakashita, Ming Li, Christine Ng, Yuhui Wang, Peter Loparco, Rafael Sierra, Lisa Wang, Blaise A Clarke, Benjamin G Neel, Lillian L Siu, Ming-Sound Tsao
PTEN inactivation occurs commonly in human cancers and putatively activates the PI3K/AKT/ mTOR pathway. Activation of this pathway has been involved in resistance to chemotherapy or anti-EGFR/HER2 therapies. We evaluated the combination of PI3K-mTOR inhibitors with chemotherapy or the pan-HER inhibitor dacomitinib in PTEN-deficient patient-derived tumor xenografts (PDX). Three PDXs were selected for their lack of PTEN expression by immunohistochemistry: a triple-negative breast cancer (TNBC), a KRAS G12R low-grade serous ovarian cancer (LGSOC), and KRAS G12C and TP53 R181P lung adenocarcinoma (LADC)...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29063517/parp-inhibitors-in-the-treatment-of-triple-negative-breast-cancer
#12
REVIEW
Jill J J Geenen, Sabine C Linn, Jos H Beijnen, Jan H M Schellens
Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis...
October 23, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28756138/mutant-p53-as-a-target-for-cancer-treatment
#13
REVIEW
Michael J Duffy, Naoise C Synnott, John Crown
TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed...
September 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28685160/next-generation-sequencing-of-circulating-tumor-dna-to-predict-recurrence-in-triple-negative-breast-cancer-patients-with-residual-disease-after-neoadjuvant-chemotherapy
#14
Yu-Hsiang Chen, Bradley A Hancock, Jeffrey P Solzak, Dumitru Brinza, Charles Scafe, Kathy D Miller, Milan Radovich
Next-generation sequencing to detect circulating tumor DNA is a minimally invasive method for tumor genotyping and monitoring therapeutic response. The majority of studies have focused on detecting circulating tumor DNA from patients with metastatic disease. Herein, we tested whether circulating tumor DNA could be used as a biomarker to predict relapse in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. In this study, we analyzed samples from 38 early-stage triple-negative breast cancer patients with matched tumor, blood, and plasma...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/28679691/metastatic-triple-negative-breast-cancer-patient-with-tp53-tumor-mutation-experienced-11-months-progression-free-survival-on-bortezomib-monotherapy-without-adverse-events-after-ending-standard-treatments-with-grade-3-adverse-events
#15
Tobias Meißner, Adam Mark, Casey Williams, Wolfgang E Berdel, Stephanie Wiebe, Andrea Kerkhoff, Eva Wardelmann, Timo Gaiser, Carsten Müller-Tidow, Philip Rosenstiel, Norbert Arnold, Brian Leyland-Jones, Andre Franke, Martin Stanulla, Michael Forster
A triple-negative breast cancer patient had no hereditary BRCA1 , BRCA2 , or TP53 risk variants. After exhaustion of standard treatments, she underwent experimental treatments and whole-exome sequencing of tumor, blood, and a metastasis. Well-tolerated experimental bortezomib monotherapy was administered for a progression-free period of 11 mo. After progression, treatments were changed and the exome data were evaluated, expanded with RNA and exome sequencing of a late-stage metastasis. In the final stage, eribulin alone and in combination with anthracyclines were administered...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28665755/depletion-of-carbonic-anhydrase-ix-abrogates-hypoxia-induced-overexpression-of-stanniocalcin-1-in-triple-negative-breast-cancer-cells
#16
Elīna Zandberga, Pawel Zayakin, Artūrs Ābols, Dārta Pūpola, Pēteris Trapencieris, Aija Linē
Carbonic anhydrase IX (CAIX) is a pH-regulating enzyme that plays a key role in maintaining an alkaline intracellular pH under hypoxic conditions. It is overexpressed in a variety of solid cancers, including breast cancer (BC), and has been implicated in the migration, invasion and stemness of breast cancer cells. Therefore, CAIX recently emerged as a novel therapeutic target for the treatment of BC. To gain an insight into the mechanism of action of CAIX inhibitors, we investigated the impact of CAIX knock-down on the transcriptional response to hypoxia in 2 BC cell lines - MCF7 and MDA-MB-231, by performing a global gene expression analysis...
August 3, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28664506/prevalence-and-spectrum-of-germline-rare-variants-in-brca1-2-and-palb2-among-breast-cancer-cases-in-sarawak-malaysia
#17
Xiaohong R Yang, Beena C R Devi, Hyuna Sung, Jennifer Guida, Eliseos J Mucaki, Yanzi Xiao, Ana Best, Lisa Garland, Yi Xie, Nan Hu, Maria Rodriguez-Herrera, Chaoyu Wang, Kristine Jones, Wen Luo, Belynda Hicks, Tieng Swee Tang, Karobi Moitra, Peter K Rogan, Michael Dean
PURPOSE: To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population. METHODS: Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site...
October 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28636652/integrative-analysis-of-genomic-alterations-in-triple-negative-breast-cancer-in-association-with-homologous-recombination-deficiency
#18
Masahito Kawazu, Shinya Kojima, Toshihide Ueno, Yasushi Totoki, Hiromi Nakamura, Akiko Kunita, Wei Qu, Jun Yoshimura, Manabu Soda, Takahiko Yasuda, Natsuko Hama, Mihoko Saito-Adachi, Kazuhito Sato, Shinji Kohsaka, Eirin Sai, Masako Ikemura, Shigeru Yamamoto, Tomoko Ogawa, Masashi Fukayama, Keiichiro Tada, Yasuyuki Seto, Shinichi Morishita, Shoichi Hazama, Tatsuhiro Shibata, Yoshihiro Yamashita, Hiroyuki Mano
Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication...
June 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28590426/down-s-syndrome-and-triple-negative-breast-cancer-a-rare-occurrence-of-distinctive-clinical-relationship
#19
Nandini Dey, Amy Krie, Jessica Klein, Kirstin Williams, Amanda McMillan, Rachel Elsey, Yuliang Sun, Casey Williams, Pradip De, Brian Leyland-Jones
Down's syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H...
June 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28539722/effect-of-helix-aspersa-extract-on-tnf%C3%AE-nf-%C3%AE%C2%BAb-and-some-tumor-suppressor-genes-in-breast-cancer-cell-line-hs578t
#20
Ibtissem El Ouar, Cornelia Braicu, Dalila Naimi, Alexendru Irimie, Ioana Berindan-Neagoe
BACKGROUND: The garden snail, Helix aspersa, is a big land snail widely found in the Mediterranean countries. It is one of the most consumed species and widely used in zootherapy. OBJECTIVE: The present study was carried out to investigate for the first time the first time the antitumor activity of an aqueous extract from Helix aspersa. MATERIALS AND METHODS: The effect of H. aspersa extract was studied on a triple negative breast cancer cell line Hs578T...
April 2017: Pharmacognosy Magazine
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