title: Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitor.
abstract: Emergence of antiestrogen-resistant cells in MCF-7 cells during suppression of estrogen signaling is a widely accepted model of acquired breast cancer resistance to endocrine therapy. To obtain insight into the genomic basis of endocrine therapy resistance, we characterized MCF-7 monoclonal sublines that survived 21-day exposure to tamoxifen (T-series sublines) or fulvestrant (F-series sublines) and sublines unselected by drugs (U-series). All T/F-sublines were resistant to the cytocidal effects of both tamoxifen and fulvestrant. However, their responses to the cytostatic effects of fulvestrant varied greatly, and their remarkably diversified morphology showed no correlation with drug resistance. mRNA expression profiles of the U-sublines differed significantly from those of the T/F-sublines, whose transcriptomal responsiveness to fulvestrant was largely lost. A set of genes strongly expressed in the U-sublines successfully predicted metastasis-free survival of breast cancer patients. Most T/F-sublines shared highly homogeneous genomic DNA aberration patterns that were distinct from those of the U-sublines. Genomic DNA of the U-sublines harbored many aberrations that were not found in the T/F-sublines. These results suggest that the T/F-sublines are derived from a common monoclonal progenitor that lost transcriptomal responsiveness to antiestrogens as a consequence of genetic abnormalities many population doublings ago, not from the antiestrogen-sensitive cells in the same culture during the exposure to antiestrogens. Thus, the apparent acquisition of antiestrogen resistance by MCF-7 cells reflects selection of preexisting drug-resistant subpopulations without involving changes in individual cells. Our results suggest the importance of clonal selection in endocrine therapy resistance of breast cancer.
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Coser
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.forename: Noël F
authors.initials: NF
authors.lastname: Rosenthal
authors.forename: Sabrina C
authors.initials: SC
authors.lastname: Collins
authors.forename: Antonia
authors.initials: A
authors.lastname: Melas
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Smith
authors.forename: Crystal J
authors.initials: CJ
authors.lastname: Mahoney
authors.forename: Keiko
authors.initials: K
authors.lastname: Shioda
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Isselbacher
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002874:Chromosome Mapping; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D020411:Oligonucleotide Array Sequence Analysis; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol
references.citation: Breast Cancer Res Treat. 2004 Feb;83(3):249-89
references.pmid: 14758095
references.citation: Nat Genet. 2003 Jan;33(1):49-54
references.pmid: 12469122
references.citation: J Clin Invest. 2007 Nov;117(11):3155-63
references.pmid: 17975657
references.citation: Breast Cancer Res Treat. 1999 Nov;58(2):87-97
references.pmid: 10674872
references.citation: BMC Bioinformatics. 2008 Aug 12;9 Suppl 9:S17
references.pmid: 18793462
references.citation: Cancer Res. 2006 Oct 15;66(20):10153-61
references.pmid: 17047080
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12033-8
references.pmid: 16882715
references.citation: Steroids. 2007 Jan;72(1):7-25
references.pmid: 17169390
references.citation: Carcinogenesis. 2008 Oct;29(10):1862-8
references.pmid: 18544561
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2351-6
references.pmid: 14983013
references.citation: Clin Cancer Res. 2004 Jan 1;10(1 Pt 2):337S-45S
references.pmid: 14734489
references.citation: Clin Cancer Res. 2008 May 15;14(10):2988-93
references.pmid: 18483364
references.citation: Cancer Cell. 2008 Feb;13(2):91-104
references.pmid: 18242510
references.citation: Lancet. 2005 Feb 19-25;365(9460):671-9
references.pmid: 15721472
references.citation: BMC Cancer. 2003 Apr 24;3:13
references.pmid: 12713671
references.citation: Cancer Genet Cytogenet. 2000 Mar;117(2):153-8
references.pmid: 10704689
references.citation: Breast Cancer Res. 2008;10(4):R68
references.pmid: 18681966
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):884s-8s
references.pmid: 15701882
references.citation: BMC Genomics. 2008 Oct 17;9:489
references.pmid: 18928532
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):13994-9
references.pmid: 14610279
references.citation: Oncogene. 2001 Oct 4;20(45):6570-8
references.pmid: 11641782
references.citation: Cancer Cell. 2006 Dec;10(6):529-41
references.pmid: 17157792
references.citation: N Engl J Med. 2002 Dec 19;347(25):1999-2009
references.pmid: 12490681
references.citation: Proc Natl Acad Sci U S A. 1987 Oct;84(20):7295-9
references.pmid: 2823256