title: ATM suppresses SATB1-induced malignant progression in breast epithelial cells.
abstract: SATB1 drives metastasis when expressed in breast tumor cells by radically reprogramming gene expression. Here, we show that SATB1 also has an oncogenic activity to transform certain non-malignant breast epithelial cell lines. We studied the non-malignant MCF10A cell line, which is used widely in the literature. We obtained aliquots from two different sources (here we refer to them as MCF10A-1 and MCF10A-2), but found them to be surprisingly dissimilar in their responses to oncogenic activity of SATB1. Ectopic expression of SATB1 in MCF10A-1 induced tumor-like morphology in three-dimensional cultures, led to tumor formation in immunocompromised mice, and when injected into tail veins, led to lung metastasis. The number of metastases correlated positively with the level of SATB1 expression. In contrast, SATB1 expression in MCF10A-2 did not lead to any of these outcomes. Yet DNA copy-number analysis revealed that MCF10A-1 is indistinguishable genetically from MCF10A-2. However, gene expression profiling analysis revealed that these cell lines have significantly divergent signatures for the expression of genes involved in oncogenesis, including cell cycle regulation and signal transduction. Above all, the early DNA damage-response kinase, ATM, was greatly reduced in MCF10A-1 cells compared to MCF10A-2 cells. We found the reason for reduction to be phenotypic drift due to long-term cultivation of MCF10A. ATM knockdown in MCF10A-2 and two other non-malignant breast epithelial cell lines, 184A1 and 184B4, enabled SATB1 to induce malignant phenotypes similar to that observed for MCF10A-1. These data indicate a novel role for ATM as a suppressor of SATB1-induced malignancy in breast epithelial cells, but also raise a cautionary note that phenotypic drift could lead to dramatically different functional outcomes.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ordinario
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Han
authors.forename: Saori
authors.initials: S
authors.lastname: Furuta
authors.forename: Laura M
authors.initials: LM
authors.lastname: Heiser
authors.forename: Lakshmi R
authors.initials: LR
authors.lastname: Jakkula
authors.forename: Francis
authors.initials: F
authors.lastname: Rodier
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kohwi
authors.forename: Terumi
authors.initials: T
authors.lastname: Kohwi-Shigematsu
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001940:Breast / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000473:pathology; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D036961:Matrix Attachment Region Binding Proteins; C076189:SATB1 protein, human; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases