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1、1NatureNature 2000 Nature Publishing GroupVolume 406(6797) 17 August 2000 pp 747-752 Molecular portraits of human breast tumours Letters to NaturePerou, Charles M.*; Srlie, Therese; Eisen, Michael B.*; van de Rijn, Matt; Jeffrey, Stefanie S./; Rees, Christian A.*; Pollack, Jonathan R.curved stem par
2、agraph sign ornament; Ross, Douglas T.curved stem paragraph sign ornament; Johnsen, Hilde; Akslen, Lars A.#; Fluge, ysteinwhite star; Pergamenschikov, Alexander*; Williams, Cheryl*; Zhu, Shirley X.; Lnning, Per E.*; Brresen- Dale, Anne-Lise; Brown, Patrick O.curved stem paragraph sign ornament; Bots
3、tein, David* Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA Department of Genetics, The Norwegian Radium Hospital, N-0310 Montebello Oslo, Norway Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA/ Departm
4、ent of Surgery, Stanford University School of Medicine, Stanford, California 94305, USAcurved stem paragraph sign ornament Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA# Department of Pathology, The Gade Institute, Haukeland University Hospital,
5、N-5021 Bergen, Norwaywhite star Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway* Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USAThese aut
6、hors contributed equally to this workReceived 7 February; accepted 25 May 2000.Correspondence and requests for materials should be addressed to D.B.(e-mail: botsteingenome.stanford.edu) or P.O.B.(e-mail: pbrowncmgm.stanford.edu).OutlineOutlineAbstract2Methods AcknowledgementsGraphicsGraphicsFigure 1
7、Figure 2Figure 3AbstractHuman breast tumours are diverse in their natural history and in their responsiveness to treatments 1. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems tran
8、sduce information from the cells identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, us
9、ing complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis
10、 from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific featu
11、res of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.We proposed that the phenotypic diversity of breast tumours might be accompanied by a corresponding diversity in gene expression patterns that we cou
12、ld capture using cDNA microarrays. Systematic investigation of gene expression patterns in human breast tumours might then provide the basis for an improved molecular taxonomy of breast cancers. We analysed gene expression patterns in grossly 3dissected normal or malignant human breast tissues from
13、42 individuals (36 infiltrating ductal carcinomas, 2 lobular carcinomas, 1 ductal carcinoma in situ, 1 fibroadenoma and 3 normal breast samples). Fluorescently labelled (Cy5) cDNA was prepared from mRNA from each experimental sample. We prepared cDNA, labelled using a second distinguishable fluoresc
14、ent nucleotide (Cy3), from a pool of mRNAs isolated from 11 different cultured cell lines (see Supplementary Information Table 1); this common reference sample provided an internal standard against which the gene expression of each experimental sample was compared 2,3.Twenty of the forty breast tumo
15、urs examined were sampled twice, as part of a larger study on locally advanced breast cancers (T3/T4 and/or N2 tumours; see ref. 4). After an open surgical biopsy to obtain the before sample, each of these patients was treated with doxorubicin for an average of 16 weeks (range 12-23), followed by re
16、section of the remaining tumour. In addition, primary tumours from two patients were also paired with a lymph node metastasis from the same patient. To help interpret the variation in expression patterns seen in the tumour samples, we also characterized 17 cultured cell lines (with one cell line cultured under three different conditions), which provided models for many
