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Title: 184AA3: a xenograft model of ER+ breast adenocarcinoma

Abstract

Despite the prevalence and significant morbidity resulting from estrogen receptor positive (ER+) breast adenocarcinomas, there are only a few models of this cancer subtype available for drug development and arguably none for studying etiology. Those models that do exist have questionable clinical relevance. Given our goal of developing luminal models, we focused on six cell lines derived by minimal mutagenesis from normal human breast cells, and asked if any could generate clinically relevant xenografts, which we then extensively characterized. Xenografts of one cell line, 184AA3, consistently formed ER+ adenocarcinomas that had a high proliferative rate and other features consistent with “luminal B” intrinsic subtype. Squamous and spindle cell/mesenchymal differentiation was absent, in stark contrast to other cell lines that we examined or others have reported. We explored intratumoral heterogeneity produced by 184AA3 by immunophenotyping xenograft tumors and cultured cells, and characterized marker expression by immunofluorescence and flow cytometry. A CD44High  subpopulation was discovered, yet their tumor forming ability was far less than CD44Low  cells. Single cell cloning revealed the phenotypic plasticity of 184AA3, consistent with the intratumoral heterogeneity observed in xenografts. Characterization of ER expression in cultures revealed ER protein and signaling is intact, yet when estrogen was depleted in culture,more » and in vivo, it did not impact cell or tumor growth, analogous to therapeutically resistant ER+  cancers. In conclusion, this model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing, and drug development.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [3];  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
  2. Univ. of Buenos Aires (Argentina). Inst. de Oncologia Angel H. Roffo, Area Investigacion
  3. Univ. of California, Davis, CA (United States). Dept. of Pathology and Laboratory Medicine and Center for Comparative Medicine
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); USDOD; National Institutes of Health (NIH)
OSTI Identifier:
1378762
Grant/Contract Number:  
AC02-05CH11231; W81XWH0810736; W81XWH12M9532; R37CA064786; R01CA140663; U54CA112970
Resource Type:
Accepted Manuscript
Journal Name:
Breast Cancer Research and Treatment
Additional Journal Information:
Journal Volume: 155; Journal Issue: 1; Journal ID: ISSN 0167-6806
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Luminal breast cancer models; Xenograft; Intratumoral heterogeneity; Microenvironment

Citation Formats

Hines, William C., Kuhn, Irene, Thi, Kate, Chu, Berbie, Stanford-Moore, Gaelen, Sampayo, Rocío, Garbe, James C., Stampfer, Martha, Borowsky, Alexander D., and Bissell, Mina J. 184AA3: a xenograft model of ER+ breast adenocarcinoma. United States: N. p., 2015. Web. doi:10.1007/s10549-015-3649-z.
Hines, William C., Kuhn, Irene, Thi, Kate, Chu, Berbie, Stanford-Moore, Gaelen, Sampayo, Rocío, Garbe, James C., Stampfer, Martha, Borowsky, Alexander D., & Bissell, Mina J. 184AA3: a xenograft model of ER+ breast adenocarcinoma. United States. doi:10.1007/s10549-015-3649-z.
Hines, William C., Kuhn, Irene, Thi, Kate, Chu, Berbie, Stanford-Moore, Gaelen, Sampayo, Rocío, Garbe, James C., Stampfer, Martha, Borowsky, Alexander D., and Bissell, Mina J. Sat . "184AA3: a xenograft model of ER+ breast adenocarcinoma". United States. doi:10.1007/s10549-015-3649-z. https://www.osti.gov/servlets/purl/1378762.
@article{osti_1378762,
title = {184AA3: a xenograft model of ER+ breast adenocarcinoma},
author = {Hines, William C. and Kuhn, Irene and Thi, Kate and Chu, Berbie and Stanford-Moore, Gaelen and Sampayo, Rocío and Garbe, James C. and Stampfer, Martha and Borowsky, Alexander D. and Bissell, Mina J.},
abstractNote = {Despite the prevalence and significant morbidity resulting from estrogen receptor positive (ER+) breast adenocarcinomas, there are only a few models of this cancer subtype available for drug development and arguably none for studying etiology. Those models that do exist have questionable clinical relevance. Given our goal of developing luminal models, we focused on six cell lines derived by minimal mutagenesis from normal human breast cells, and asked if any could generate clinically relevant xenografts, which we then extensively characterized. Xenografts of one cell line, 184AA3, consistently formed ER+ adenocarcinomas that had a high proliferative rate and other features consistent with “luminal B” intrinsic subtype. Squamous and spindle cell/mesenchymal differentiation was absent, in stark contrast to other cell lines that we examined or others have reported. We explored intratumoral heterogeneity produced by 184AA3 by immunophenotyping xenograft tumors and cultured cells, and characterized marker expression by immunofluorescence and flow cytometry. A CD44High  subpopulation was discovered, yet their tumor forming ability was far less than CD44Low  cells. Single cell cloning revealed the phenotypic plasticity of 184AA3, consistent with the intratumoral heterogeneity observed in xenografts. Characterization of ER expression in cultures revealed ER protein and signaling is intact, yet when estrogen was depleted in culture, and in vivo, it did not impact cell or tumor growth, analogous to therapeutically resistant ER+  cancers. In conclusion, this model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing, and drug development.},
doi = {10.1007/s10549-015-3649-z},
journal = {Breast Cancer Research and Treatment},
number = 1,
volume = 155,
place = {United States},
year = {2015},
month = {12}
}

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    Works referencing / citing this record:

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