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Constitutive CCND1/CDK2 Activity Substitutes for p53 Loss, or MYC or Oncogenic RAS Expression in the Transformation of Human Mammary Epithelial Cells

Journal Article · · PLoS ONE
 [1];  [2];  [3];  [4]
  1. Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Pathology; DOE/OSTI
  2. Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Pathology
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  4. Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Pathology; Case Western Reserve Univ., Cleveland, OH (United States). Case Comprehensive Cancer Center
+ Show Author Affiliations
Cancer develops following the accumulation of genetic and epigenetic alterations that inactivate tumor suppressor genes and activate proto-oncogenes. Dysregulated cyclin-dependent kinase (CDK) activity has oncogenic potential in breast cancer due to its ability to inactivate key tumor suppressor networks and drive aberrant proliferation. Accumulation or overexpression of cyclin D1 (CCND1) occurs in a majority of breast cancers and over-expression of CCND1 leads to accumulation of activated CCND1/CDK2 complexes in breast cancer cells. We describe here the role of constitutively active CCND1/CDK2 complexes in human mammary epithelial cell (HMEC) transformation. A genetically-defined, stepwise HMEC transformation model was generated by inhibiting p16 and p53 with shRNA, and expressing exogenous MYC and mutant RAS. By replacing components of this model, we demonstrate that constitutive CCND1/CDK2 activity effectively confers anchorage independent growth by inhibiting p53 or replacing MYC or oncogenic RAS expression. These findings are consistent with several clinical observations of luminal breast cancer sub-types that show elevated CCND1 typically occurs in specimens that retain wild-type p53, do not amplify MYC, and contain no RAS mutations. Taken together, these data suggest that targeted inhibition of constitutive CCND1/CDK2 activity may enhance the effectiveness of current treatments for luminal breast cancer.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1627577
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 2 Vol. 8; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (8)

Mutant p53 dictates the oncogenic activity of c-Abl in triple-negative breast cancers journal June 2017
Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling journal March 2017
A FAM83A Positive Feed-back Loop Drives Survival and Tumorigenicity of Pancreatic Ductal Adenocarcinomas journal September 2019
Disrupting MLV integrase:BET protein interaction biases integration into quiescent chromatin and delays but does not eliminate tumor activation in a MYC/Runx2 mouse model journal December 2019
Role of p27Kip1 as a transcriptional regulator journal May 2018
Inferring Protein Modulation from Gene Expression Data Using Conditional Mutual Information text January 2014
Transcriptional Profiling of Laser Capture Microdissected Subpopulations of the Osteoblast Lineage Provides Insight Into the Early Response to Sclerostin Antibody in Rats journal May 2015
Inferring Protein Modulation from Gene Expression Data Using Conditional Mutual Information journal October 2014

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