scholarly journals Frame-shift mediated reduction of gain-of-function p53 R273H and deletion of the R273H C-terminus in breast cancer cells result in replication-stress sensitivity

Oncotarget ◽  
2021 ◽  
Author(s):  
Viola Ellison ◽  
George K. Annor ◽  
Clara Freedman ◽  
Gu Xiao ◽  
Devon Lundine ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Replication Stress ◽  
Stress Sensitivity ◽  
Gain Of Function ◽  
Frame Shift ◽  
C Terminus ◽  
Mediated Reduction

The HMGB1 C Terminus is Indispensable for the Chemotaxis Tested on Breast Cancer Cells

2018 ◽  
Author(s):  
Evdokia Pasheva ◽  
Maria Schröder ◽  
Shazie Yusein-Myashkova ◽  
Jordana Todorova ◽  
Iva Ugrinova
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
C Terminus

scholarly journals Extracellular Matrix Enhances Heregulin-Dependent BRCA1 Phosphorylation and Suppresses BRCA1 Expression through Its C Terminus

2003 ◽  
Vol 23 (2) ◽  
pp. 579-593 ◽  
Author(s):  
Tiho Miralem ◽  
Hava Karsenty Avraham
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Wild Type ◽  
Brca1 Expression ◽  
T47d Cells ◽  
C Terminus ◽  
Brca1 Mrna

ABSTRACT Germ line mutations in the breast cancer susceptibility gene BRCA1 account for the increased risk of early onset of familial breast cancer, whereas overexpression of the ErbB family of receptor tyrosine kinases has been linked to the development of nonfamilial or sporadic breast cancer. To analyze whether there is a link between these two regulatory molecules, we studied the effects of ErbB-2 activation by heregulin (HRG) on BRCA1 function. It was previously demonstrated that HRG induced the phosphorylation of BRCA1, which was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Since altered interaction between cells and the surrounding extracellular matrix (ECM) is a common feature in a variety of tumors and since ECM modulates intracellular signaling, we hypothesized that ECM may affect the expression and HRG-dependent phosphorylation of BRCA1. Following stimulation by HRG, a strong increase in [3H]thymidine incorporation was observed in human T47D breast cancer cells seeded on plastic (PL). When T47D cells were seeded on laminin (LAM) or Matrigel, HRG induced a significantly higher proliferation than it did in cells seeded on PL. T47D cells seeded on poly-l-lysine had an abrogated mitogenic response, indicating the involvement of integrins in this process. HRG treatment induced a transient phosphorylation of BRCA1 that was enhanced in T47D cells grown on LAM. LAM-enhanced BRCA1 phosphorylation was mediated through α6 integrin upon HRG stimulation. Accordingly, T47D cells grown on LAM had the greatest increase in ErbB-2 activation, PI3K activity, and phosphorylation of Akt. A similar pattern of BRCA1 mRNA expression was observed when T47D cells were seeded on PL, LAM, or COL4. There was a significant decrease in the steady state of the BRCA1 mRNA level on both the LAM and COL4 matrices compared to that for cells seeded on PL. In addition, HRG stimulation caused a significant decrease in BRCA1 mRNA expression that was dependent on protein synthesis. Pretreatment with both the calpain inhibitor ALLN (N-acetyl-Leu-Leu-norleucinal) and the proteosome inhibitor lactacystin inhibited the HRG-induced down-regulation of BRCA1 mRNA expression. Likewise, there was a strong decrease in the protein level of BRCA1 in T47D cells 4 h after treatment with HRG compared to its level in control nontreated T47D cells. Pretreatment with the proteosome inhibitors ALLN, lactacystin, and PSI [N-benzyloxycarbonyl-Ile-Glu-(O-t-butyl)-Ala-leucinal] inhibited also the HRG-induced down-regulation of BRCA1 protein in breast cancer cells. Interestingly, BRCA1 mRNA expression in HCC-1937 breast cancer cells, which express C-terminally truncated BRCA1, was not affected by either LAM or CL4. No phosphorylation of BRCA1 from HCC-1937 cells was observed in response to HRG. While Cdk4 phosphorylated wild-type BRCA1 in response to HRG in T47D cells, Cdk4 failed to phosphorylate the truncated form of BRCA1 in HCC-1937 cells. Furthermore, overexpression of wild-type BRCA1 in HCC-1937 cells resulted in the phosphorylation of BRCA1 and decreased BRCA1 expression upon HRG stimulation while overexpression of truncated BRCA1 in T47D cells resulted in a lack of BRCA1 phosphorylation and restoration of BRCA1 expression. These findings suggest that ECM enhances HRG-dependent BRCA1 phosphorylation and that ECM and HRG down-regulate BRCA1 expression in breast cancer cells. Furthermore, ECM suppresses BRCA1 expression through the C terminus of BRCA1.

scholarly journals Identification of a novel opioid peptide (Tyr-Val-Pro-Phe-Pro) derived from human αS1 casein (αS1-casomorphin, and αS1-casomorphin amide)

1996 ◽  
Vol 319 (3) ◽  
pp. 903-908 ◽  
Author(s):  
Marilenna KAMPA ◽  
Spyros LOUKAS ◽  
Anastassia HATZOGLOU ◽  
Patrice MARTIN ◽  
Pierre-Marie MARTIN ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Somatostatin Receptors ◽  
T47d Cell ◽  
Opioid Peptide ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
C Terminus ◽  
Dose Dependent

A new casomorphin pentapeptide (αS1-casomorphin) has been isolated from the sequence of human αS1-casein [αS1-casein-(158–162)], with the sequence Tyr-Val-Pro-Phe-Pro. This peptide was found to bind with high affinity to all three subtypes of the κ-opioid receptor (κ1–κ3). When amidated at the C-terminus, αS1-casomorphin amide binds to the Δ- and κ3-opioid sites. Both αS1-casomorphin and its amide inhibit in a dose-dependent and reversible manner the proliferation of T47D human breast cancer cells. This anti-proliferative activity was greater for αS1-casomorphin, which was the most potent opioid in inhibiting T47D cell proliferation. In T47D breast cancer cells, other casomorphins have been found to bind to somatostatin receptors in addition to opioid sites. In contrast, αS1-casomorphin and its amide do not interact with somatostatin receptors in our system.

scholarly journals Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress

Oncotarget ◽  
2016 ◽  
Vol 7 (23) ◽  
pp. 34688-34702 ◽  
Author(s):  
Yao Zhang ◽  
Jinzhi Lai ◽  
Zhanwen Du ◽  
Jinnan Gao ◽  
Shuming Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Replication Stress ◽  
Chk1 Inhibitor

Gain-of-function mutant p53-R280K mediates survival of breast cancer cells

2013 ◽  
Vol 36 (2) ◽  
pp. 171-178 ◽  
Author(s):  
Yun-Hee Bae ◽  
Jong-Myung Shin ◽  
Hyun-Joo Park ◽  
Hye-Ock Jang ◽  
Moon-Kyoung Bae ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mutant P53 ◽  
Gain Of Function

scholarly journals NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation

2020 ◽  
Author(s):  
Daniel Haber ◽  
Hongshan Guo ◽  
Gabriel Golczer ◽  
Ben Wittner ◽  
Adam Langenbucher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Large Fraction ◽  
Replication Stress ◽  
Early Gene ◽  
Immediate Early ◽  
Mitotic Catastrophe ◽  
Open Chromatin ◽  
Transcriptional Elongation

Abstract Deregulation of oncogenic proliferative signals triggers replication stress in cancer cells to which they must adapt1,2. Immediate early genes (IEGs), identified by their rapid stress-induced transient bursts of expression, are critical to integrating downstream signaling pathways3,4. In studying tumor initiation by patient-derived breast cancer cells, we observed acquisition of open chromatin domains at the genebody and 3’-UTR of IEGs, uniquely across the genome. Through in vivo and in vitro modeling, we show that the IEG and orphan nuclear receptor NR4A15 localizes across multiple IEG genebodies, where it binds to RNA Pol II, arresting transcriptional elongation and generating extensive R-loops and accessible chromatin. Acute stress promptly removes NR4A1 from IEG genebodies, triggering immediate release of their poised transcripts. In breast cancer cells, NR4A1 overexpression increases tumorigenesis; conversely, its deletion leads to uncompensated replication stress, chromosomal instability and mitotic catastrophe, driven by deregulation of its IEG target FOS. A large fraction of primary breast and other cancers exhibit open genebody chromatin at IEGs, consistent with preserved NR4A1 function. Thus, NR4A1 mediates a novel transcriptional elongation checkpoint, unique to stress-induced genes and required for their rapid bursts of expression. Cancers that have retained this mechanism in adapting to chronic replication stress may be dependent on NR4A1 for proliferation.

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