scholarly journals Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels

2018 ◽  
Author(s):  
Jonathan P Rennhack ◽  
Matthew Swiatnicki ◽  
Yueqi Zhang ◽  
Caralynn Li ◽  
Evan Bylett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Cancer Patients ◽  
Mouse Models ◽  
Copy Number ◽  
Human Breast Cancer ◽  
Human Cancer ◽  
Copy Number Alterations ◽  
Human Breast ◽  
Lung Cancer Patients

AbstractMouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. However, the shared genomic alterations in each model and corresponding human cancer are critical for translating findings in mice to the clinic. We have completed whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. This genomic information was integrated with phenotypic data and CRISPR/Cas9 studies to understand the impact of key events on tumor biology. Despite the engineered initiating transgenic event in these mouse models, they contain similar copy number alterations, single nucleotide variants, and translocation events as human breast cancer. Through integrative in vitro and in vivo studies, we identified copy number alterations in key extracellular matrix proteins including Collagen 1 Type 1 alpha 1 (Col1a1) and Chondroadherin (CHAD) that drive metastasis in these mouse models. Importantly this amplification is also found in 25% of HER2+ human breast cancer and is associated with increased metastasis. In addition to copy number alterations, we observed a propensity of the tumors to modulate tyrosine kinase mediated signaling through mutation of phosphatases. Specifically, we found that 81% of MMTV-PyMT tumors have a mutation in the EGFR regulatory phosphatase, PTPRH. Mutation in PTPRH led to increased phospho-EGFR levels and decreased latency. Moreover, PTPRH mutations increased response to EGFR kinase inhibitors. Analogous PTPRH mutations are present in lung cancer patients and together this data suggests that a previously unidentified population of human lung cancer patients may respond to EGFR targeted therapy. These findings underscore the importance of understanding the complete genomic landscape of a mouse model and illustrate the utility this has in understanding human cancers.

Copy Number Alterations that Predict Metastatic Capability of Human Breast Cancer

2009 ◽  
Vol 69 (9) ◽  
pp. 3795-3801 ◽  
Author(s):  
Yi Zhang ◽  
John W.M. Martens ◽  
Jack X. Yu ◽  
John Jiang ◽  
Anieta M. Sieuwerts ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Human Breast Cancer ◽  
Copy Number Alterations ◽  
Human Breast

Design, Synthesis and Antitumor Assessment of Phenylureas Bearing 5-Fluoroindolin-2-one Moiety

2020 ◽  
Vol 16 (7) ◽  
pp. 958-968
Author(s):  
Yunrui Cai ◽  
Tong Chen ◽  
Huajian Zhu ◽  
Hongbin Zou
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Human Cancer ◽  
The Body ◽  
Human Breast ◽  
Design Synthesis ◽  
Human Carcinoma ◽  
Xenograft Models ◽  
New Compounds ◽  
Mcf 7

Background: The development of novel antineoplastic agents remains highly desirable. Objective: This study focuses on the design, synthesis, and antitumor evaluation of phenyl ureas bearing 5-fluoroindolin-2-one moiety. Methods: Three sets of phenylureas were designed and synthesized and their antiproliferative ability was measured against four human carcinoma cell lines (Hela, Eca-109, A549, and MCF-7) via MTT assay. In vivo anticancer activity was further evaluated in xenograft models of human breast cancer (MCF-7). Results: A total of twenty-one new compounds were synthesized and characterized by means of 1H and 13C NMR as well as HR-MS. Three sets of compounds (1a‒1c, 2a‒2c, and 3a‒3c) were initially constructed, and preliminary antiproliferative activities of these molecules were evaluated against Hela, Eca-109, A549 and MCF-7, highlighting the meta-substituted phenylureas (1a‒1c) as the most cytotoxic set. A series of meta-substituted phenylureas derivatives (1d‒1o) were then designed and synthesized for structure-activity relationship study. Most of the new compounds showed desirable cytotoxicity, among which compound 1g exhibited the most remarkable cytotoxic effects against the tested human cancer cells with IC50 values ranging from 1.47 to 6.79 μM. Further studies showed that compound 1g suppressed tumor growth in human breast cancer (MCF- 7) xenograft models without affecting the body weight of its recipients. Conclusion: In this study, twenty-one new compounds, containing the privileged structures of phenylurea and 5-fluoroindolin-2-one, were designed and synthesized. Subsequent structureactivity studies showed that 1g was the most bioactive antitumor agent among all tested compounds, hence a potentially promising lead compound once given further optimization.

scholarly journals Antiestrogen-resistant human breast cancer cells require activated Protein Kinase B/Akt for growth

2005 ◽  
Vol 12 (3) ◽  
pp. 599-614 ◽  
Author(s):  
T Frogne ◽  
J S Jepsen ◽  
S S Larsen ◽  
C K Fog ◽  
B L Brockdorff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cell Lines ◽  
Human Breast Cancer ◽  
Neutralizing Antibodies ◽  
Breast Cancer Cells ◽  
Resistant Cell ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Mcf 7

Development of acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. The IGF system plays a profound role in many cancer types, including breast cancer. Thus, overexpression and/or constitutive activation of the IGF-I receptor (IGF-IR) or different components of the IGF-IR signaling pathway have been reported to render breast cancer cells less estrogen dependent and capable of sustaining cell proliferation in the presence of antiestrogens. In this study, growth of the antiestrogen-sensitive human breast cancer cell line MCF-7 was inhibited by treatment with IGF-IR-neutralizing antibodies. In contrast, IGF-IR-neutralizing antibodies had no effect on growth of two different antiestrogen-resistant MCF-7 sublines. A panel of antiestrogen-resistant cell lines was investigated for expression of IGF-IR and either undetectable or severely reduced IGF-IR levels were observed. No increase in insulin receptor substrate 1 (IRS-1) or total PKB/Akt (Akt) was detected in the resistant cell lines. However, a significant increase in phosphorylated Akt (pAkt) was found in four of six antiestrogen-resistant cell lines. Overexpression of pAkt was associated with increased Akt kinase activity in both a tamoxifen- and an ICI 182,780-resistant cell line. Inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin or the Akt inhibitor SH-6 (structurally modified phosphatidyl inositol ether liquid analog PIA 6) resulted in a more pronounced growth inhibitory effect on the antiestrogen-resistant cells compared with the parental cells, suggesting that signaling via Akt is required for antiestrogen-resistant cell growth in at least a subset of our antiestrogen-resistant cell lines. PTEN expression and activity was not decreased in cell lines overexpressing pAkt. Our data demonstrate that Akt is a target for treatment of antiestrogen-resistant breast cancer cell lines and we suggest that antiestrogen-resistant breast cancer patients may benefit from treatment targeted to inhibit Akt signaling.

scholarly journals MMTV mouse models and the diagnostic values of MMTV-like sequences in human breast cancer

2009 ◽  
Vol 9 (5) ◽  
pp. 423-440 ◽  
Author(s):  
Pankaj Taneja ◽  
Donna P Frazier ◽  
Robert D Kendig ◽  
Dejan Maglic ◽  
Takayuki Sugiyama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Models ◽  
Human Breast Cancer ◽  
Human Breast ◽  
Diagnostic Values

Detection of copy number alteration of MTA1 in human breast cancer

2009 ◽  
Vol 6 (4) ◽  
pp. 245-249
Author(s):  
Mengquan Li ◽  
Jingruo Li ◽  
Mingxun Chen ◽  
Juntao Bao
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Human Breast Cancer ◽  
Copy Number Alteration ◽  
Human Breast

Prognostic and predictive value of 16p12.1 and 16q22.1 copy number changes in human breast cancer

2010 ◽  
Vol 198 (1) ◽  
pp. 52-61 ◽  
Author(s):  
Tricia E. Downing ◽  
Maja H. Oktay ◽  
Melissa J. Fazzari ◽  
Cristina Montagna
Keyword(s):  
Breast Cancer ◽  
Predictive Value ◽  
Copy Number ◽  
Human Breast Cancer ◽  
Human Breast ◽  
Copy Number Changes

scholarly journals High Levels of Chromosomal Copy Number Alterations and TP53 Mutations Correlate with Poor Outcome in Younger Breast Cancer Patients

2020 ◽  
Vol 190 (8) ◽  
pp. 1643-1656
Author(s):  
Ayla Koçak ◽  
Kerstin Heselmeyer-Haddad ◽  
Annette Lischka ◽  
Daniela Hirsch ◽  
David Fiedler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Breast Cancer Patients ◽  
Tp53 Mutations ◽  
Poor Outcome ◽  
Chromosomal Copy Number ◽  
Chromosomal Copy

scholarly journals Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel

2016 ◽  
Vol 18 (4) ◽  
pp. 486-496 ◽  
Author(s):  
Ho Jeong Lee ◽  
Masaki Hanibuchi ◽  
Sun-Jin Kim ◽  
Hyunkyung Yu ◽  
Mark Seungwook Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Brain Metastases ◽  
Human Breast Cancer ◽  
Endothelin Receptors ◽  
Human Breast
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