scholarly journals Principles governing A-to-I RNA editing in the breast cancer transcriptome

2014 ◽  
Author(s):  
Debora Fumagalli ◽  
David Gacquer ◽  
Françoise Rothé ◽  
Anne Lefort ◽  
Frederick Libert ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Rna Editing ◽  
Cell Lines ◽  
Normal Breast ◽  
The Cancer Genome Atlas ◽  
Interferon Response ◽  
Breast Cancer Cell Lines ◽  
Type I ◽  
Breast Cancers ◽  
Cancer Transcriptome

A-to-I editing substitutes inosines for adenosines at specific positions in mRNAs and can substantially alter a cell's transcriptome. Currently, little is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. Controlled ADAR expression experiments demonstrated that the editing frequency at all loci is proportional to both ADAR expression levels and the individual locus' editability?a propensity to be edited determined by the surrounding nucleotide sequence. Comparison of tumor transcriptomes to those of normal breast and breast organoids, i.e. pure normal breast epithelial cells, demonstrated that the editing frequency is increased in tumor cells. This was consistent with ADAR immunohistochemistry. We also demonstrated that type I interferon response and ADAR DNA copy number explain together 53% of ADAR expression in breast cancers, an observation also valid in nearly all of 20 other cancer types in The Cancer Genome Atlas. Interferon exposure increased ADAR mRNA, protein expression and editing in four breast cell lines. Finally, ADAR silencing using shRNA lentivirus transduction in breast cancer cell lines led to more cell proliferation and less apoptosis. Our results reveal that A-to-I editing is a pervasive, yet reproducible, source of variation that is controlled by two factors, 1q amplification and inflammation, both highly prevalent among human cancers. This suggests the potential for a new class of therapeutic targets and an unexpected role for inflammation in cancers.

Cathepsin D concentration in breast cancer cytosols: correlation with biochemical, histological, and clinical findings

1991 ◽  
Vol 37 (1) ◽  
pp. 101-104 ◽  
Author(s):  
M J Duffy ◽  
J P Brouillet ◽  
D Reilly ◽  
E McDermott ◽  
N O'Higgins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cathepsin D ◽  
Tumor Grade ◽  
Tumor Stage ◽  
Normal Breast ◽  
Axillary Node ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Lysosomal Protease

Abstract Cathepsin D (CD, EC 3.4.23.5) is a lysosomal protease induced by estrogen in certain estrogen receptor (ER)-positive breast cancer cell lines but produced constitutively by ER-negative cell lines. Our aims in this investigation were to study the distribution of CD in human breast cancers and to relate its concentrations to various biochemical, histological, and clinical characteristics. The concentrations of CD were significantly higher in breast carcinomas than in either normal breast tissues or benign breast tumors. In primary carcinomas, CD concentrations did not correlate with the concentrations of ER or with the estrogen-inducible protease t-PA. However, CD concentrations did correlate weakly but significantly with both UK-PA antigen and UK-PA activity. Also, CD concentrations did not correlate with either tumor stage or axillary node status but did correlate significantly with tumor grade. Patients with cancers containing high concentrations of CD had a significantly shorter overall survival than did patients with low concentrations of the enzyme.

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals Extracellular Calcium-Sensing Receptor Expression and Its Potential Role in Regulating Parathyroid Hormone-Related Peptide Secretion in Human Breast Cancer Cell Lines*

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4357-4364 ◽  
Author(s):  
Jennifer L. Sanders ◽  
Naibedya Chattopadhyay ◽  
Olga Kifor ◽  
Toru Yamaguchi ◽  
Robert R. Butters ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Cancer Cell Lines ◽  
Human Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Breast

Abstract Metastasis of breast cancer to bone occurs with advanced disease and produces substantial morbidity. Secretion of PTH-related peptide (PTHrP) from breast cancer cells is thought to play a key role in osteolytic metastases and is increased by transforming growth factor-β (TGFβ), which is released from resorbed bone. Elevated extracellular calcium (Cao2+) also stimulates PTHrP secretion from various normal and malignant cells, an action that could potentially be mediated by the Cao2+-sensing receptor (CaR) originally cloned from the parathyroid gland. Indeed, we previously showed that both normal breast ductal epithelial cells and primary breast cancers express the CaR. In this study we investigated whether the MCF-7 and MDA-MB-231 human breast cancer cell lines express the CaR and whether CaR agonists modulate PTHrP secretion. Northern blot analysis and RT-PCR revealed bona fide CaR transcripts, and immunocytochemistry and Western analysis with a specific anti-CaR antiserum demonstrated CaR protein expression in both breast cancer cell lines. Furthermore, elevated Cao2+ and the polycationic CaR agonists, neomycin and spermine, stimulated PTHrP secretion dose dependently, with maximal, 2.1- to 2.3-fold stimulation. In addition, pretreatment of MDA-MB-231 cells overnight with TGFβ1 (0.2, 1, or 5 ng/ml) augmented both basal and high Cao2+-stimulated PTHrP secretion. Thus, in PTHrP-secreting breast cancers metastatic to bone, the CaR could potentially participate in a vicious cycle in which PTHrP-induced bone resorption raises the levels of Cao2+ and TGFβ within the bony microenvironment, which then act in concert to evoke further PTHrP release and worsening osteolysis.

scholarly journals Selective Effects of Thioridazine on Self-Renewal of Basal-Like Breast Cancer Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Matthew Tegowski ◽  
Cheng Fan ◽  
Albert S. Baldwin
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Types ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Self Renewal ◽  
Basal Like Breast Cancer

AbstractSeveral recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.

scholarly journals Quantification of prolactin receptor mRNA in multiple human tissues and cancer cell lines by real time RT-PCR

2001 ◽  
Vol 171 (1) ◽  
pp. R1-R4 ◽  
Author(s):  
SK Peirce ◽  
WY Chen ◽  
WY Chen
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Normal Breast ◽  
Breast Cancer Cell Lines ◽  
Human Tissues ◽  
Normal Human

Human prolactin (hPRL) has been reported to be involved in breast and prostate cancer development. The hPRL receptor (hPRLR) is expressed in a wide variety of tissues in at least three isoforms. In this study, a one-step real time reverse transcription PCR technique was used to determine relative expression levels of hPRLR mRNA in eleven human breast cancer cell lines, HeLa cells, three prostate cancer cell lines and nine normal human tissues. The housekeeping gene beta-actin was used for internal normalization. We demonstrate that hPRLR mRNA is up-regulated in six of the eleven breast cancer cell lines tested when compared with normal breast tissue. Of the cancer cell lines tested, we found that T-47D cells have the highest level of hPRLR mRNA, followed by MDA-MB-134, BT-483, BT-474, MCF-7 and MDA-MB-453 cells. In two breast cancer cell lines (MDA-MB-468 and BT-549), the hPRLR levels were found to be comparable to that of normal breast tissue. Three breast cancer cell lines (MDA-MB-436, MDA-MB-157 and MDA-MB-231) expressed hPRLR mRNA at levels lower than that of normal tissue. In contrast, in all three commonly used prostate cancer cell lines (LNCaP, PC-3 and DU 145), the levels of hPRLR mRNA were found to be down-regulated relative to that of normal prostate tissue. Of nine normal human tissues tested, we found that the uterus and the breast have the highest levels of hPRLR mRNA, followed by the kidney, the liver, the prostate and the ovary. The levels of hPRLR mRNA were the lowest among the trachea, the brain and the lung.

scholarly journals New generation breast cancer cell lines developed from patient-derived xenografts

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Jessica Finlay-Schultz ◽  
Britta M. Jacobsen ◽  
Duncan Riley ◽  
Kiran V. Paul ◽  
Scott Turner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Luminal A ◽  
New Generation

Abstract Background Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics. Methods Established breast cancer PDX were processed into cell suspensions and placed into standard 2D cell culture; six emerged into long-term passageable cell lines. Cell lines were assessed for protein expression of common luminal, basal, and mesenchymal markers, growth assessed in response to estrogens and endocrine therapies, and RNA-seq and oncogenomics testing performed to compare relative transcript levels and identify putative oncogenic drivers. Results Three cell lines express ER and two are also progesterone receptor (PR) positive; PAM50 subtyping identified one line as luminal A. One of the ER+PR+ lines harbors a D538G mutation in the gene for ER (ESR1), providing a natural model that contains this endocrine-resistant genotype. The third ER+PR−/low cell line has mucinous features, a rare histologic type of breast cancer. The three other lines are ER− and represent two basal-like and a mixed ductal/lobular breast cancer. The cell lines show varied responses to tamoxifen and fulvestrant, and three were demonstrated to regrow tumors in vivo. RNA sequencing confirms all cell lines are human and epithelial. Targeted oncogenomics testing confirmed the noted ESR1 mutation in addition to other mutations (i.e., PIK3CA, BRCA2, CCND1, NF1, TP53, MYC) and amplifications (i.e., FGFR1, FGFR3) frequently found in breast cancers. Conclusions These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.

scholarly journals Role of secreted type I collagen derived from stromal cells in two breast cancer cell lines

2014 ◽  
Vol 8 (2) ◽  
pp. 507-512 ◽  
Author(s):  
SUNG HOON KIM ◽  
HYE YOON LEE ◽  
SEUNG PIL JUNG ◽  
SANGMIN KIM ◽  
JEONG EON LEE ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Stromal Cells ◽  
Type I Collagen ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Type I

scholarly journals MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5979
Author(s):  
Diana E. Baxter ◽  
Lisa M. Allinson ◽  
Waleed S. Al Amri ◽  
James A. Poulter ◽  
Arindam Pramanik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cell Lines ◽  
Target Genes ◽  
Breast Cancer Cell Lines ◽  
Molecular Characteristics ◽  
Chemotherapy Response ◽  
Breast Cancers ◽  
Microrna Target ◽  
Estrogen Receptor Positive

Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies.

scholarly journals The synthetic histone-binding regulator protein PcTF activates interferon genes in breast cancer cells

2017 ◽  
Author(s):  
Kimberly C. Olney ◽  
David B. Nyer ◽  
Daniel A. Vargas ◽  
Melissa A. Wilson Sayres ◽  
Karmella A. Haynes
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Transcriptional Response ◽  
Transcriptome Profiling ◽  
Interferon Response ◽  
Breast Cancer Cell Lines ◽  
Binding Motif ◽  
Histone Marks ◽  
Model Cell ◽  
Treated Breast

ABSTRACTMounting evidence from genome-wide studies of cancer show that chromatin-mediated epigenetic silencing at large cohorts of genes is strongly linked to a poor prognosis. This mechanism is thought to prevent cell differentiation and enable evasion of the immune system. Drugging the cancer epigenome with small molecule inhibitors to release silenced genes from the repressed state has emerged as a powerful approach for cancer research and drug development. Targets of these inhibitors include chromatin-modifying enzymes that can acquire drug-resistant mutations. In order to directly target a generally conserved feature, elevated trimethyl-lysine 27 on histone H3 (H3K27me3), we developed the Polycomb-based Transcription Factor (PcTF), a fusion activator that targets methyl-histone marks via its N-terminal H3K27me3-binding motif, and co-regulates sets of silenced genes. Here, we report transcriptome profiling analyses of PcTF-treated breast cancer model cell lines. We identified a set of 19 PcTF-upregulated genes, or PUGs, that were consistent across three distinct breast cancer cell lines. These genes are associated with the interferon response pathway. Our results demonstrate for the first time a chromatin-mediated interferon-related transcriptional response driven by an engineered fusion protein that physically links repressive histone marks with active transcription.

scholarly journals Deep Whole Genome Sequencing Identifies Recurrent Genomic Alterations in Commonly-Used Breast Cancer Cell Lines and Patient Derived Xenograft Models

2021 ◽  
Author(s):  
Niantao Deng ◽  
Andre Minoche ◽  
Kate Harvey ◽  
Meng Li ◽  
Juliane Winkler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Cell Lines ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Whole Genome ◽  
Breast Cancers ◽  
Pdx Models

Abstract Background: Breast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Deep whole genome sequencing is the most sensitive and accurate method to detect single nucleotide variants and indels, gene copy number and structural events such as gene fusions.Results: Here we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage. We identify novel genomic alterations, including point mutations and genomic rearrangements at base-pair resolution, compared to previously available sequencing data. Through integrative analysis with publicly available functional screening data, we annotate new genomic features likely to be of biological significance. CSMD1, previously identified as a tumor suppressor gene in various cancer types, including head and neck, lung and breast cancers, has been identified with deletion in 50% of our PDX models, suggesting an important role in aggressive breast cancers. Conclusions: Our WGS data provides a comprehensive genome sequencing resource of these models.

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