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 CD44(High) subpopulation was discovered, yet their tumor forming ability was far less than CD44(Low) 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. This model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing, and drug development.
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA. CHines@LBL.GOV.
authors.forename: William C
authors.initials: WC
authors.lastname: Hines
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Kuhn
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Thi
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
authors.forename: Berbie
authors.initials: B
authors.lastname: Chu
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
authors.forename: Gaelen
authors.initials: G
authors.lastname: Stanford-Moore
authors.affiliation: Área Investigación, Instituto de Oncología Angel H. Roffo-UBA, Buenos Aires, Argentina.
authors.forename: Rocío
authors.initials: R
authors.lastname: Sampayo
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Garbe
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Stampfer
authors.affiliation: Department of Pathology and Laboratory Medicine and Center for Comparative Medicine, University of California, Davis, Davis, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Mailstop 977R225A, 1 Cyclotron Road, Berkeley, CA, 94720, USA. MJBissell@LBL.GOV.
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D011960:Receptors, Estrogen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D011960:Receptors, Estrogen
keywords: Intratumoral heterogeneity; Luminal breast cancer models; Microenvironment; Xenograft