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A New Breast Tumor Intrinsic Gene List Identifies Novel Characteristics that are Conserved Across Microarray Platforms

ABSTRACT: Breast cancer is a difficult disease to manage because it is comprised of a spectrum of tumor subtypes with different biological characteristics. Previous gene expression studies using breast tumor “intrinsic” gene lists identified five distinct subtypes of breast tumors: Luminal A, Luminal B, Normal Breast-like, HER2+/ER- and Basal-like. Using a training data set of 102 unique breast tumors, we derive a new “intrinsic” gene list based upon 26 paired samples. This Intrinsic/UNC gene set recapitulates the old classifications and extends the analysis to include a large proliferation signature, which was lacking before. Using Distance Weighted Discrimination, we next created a true “test set” of 311 tumors by combining together three different publicly available breast tumor microarray data sets (1-3), which was then analyzed using the newly derived Intrinsic/UNC gene set. The test set analysis identified the same five intrinsic subtypes seen before and a new one (Luminal I), and we show that the intrinsic subtype classifications are independent predictors of relapse-free survival when adjusting for age, node status, tumor size, grade and ER status. We also developed a “Single Sample Predictor” that is able to assign an intrinsic subtype to one sample at a time, which was also shown to be predictive of outcomes on another independent test set of tamoxifen-treated ER+ patients. These analyses demonstrate that 1) common patterns of expression can be identified across different microarray platforms, 2) the breast tumor “intrinsic” subtypes are present in all breast tumor data sets studied, and 3) this classification is adding value to the existing repertoire of clinical markers for breast cancer patients. Keywords: parallel sample

ORGANISM(S): Homo sapiens

PROVIDER: GSE1992 | GEO | 2005/12/08

SECONDARY ACCESSION(S): PRJNA91007

REPOSITORIES: GEO

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Project description:Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favourable patient prognosis, which is in part, attributed to the Estrogen Receptor-alpha (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favourable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer. FOXA1 siRNA treated breast cell lines compared directly to nonspecific siRNA treated cell lines using Agilent 4X44 microarrays.

Project description:Breast cancer is a profoundly heterogeneous disease with respect to biological and clinical behavior. Gene expression profiling has been used to dissect this complexity and stratify tumors into intrinsic gene expression subtypes associated with distinct biology, patient outcome and different genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. We applied global DNA copy number and gene expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy number aberrations and genomic subgroups of breast cancer. We identified 31 genomic regions that were highly amplified in >1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions (66 and 67 with DNA copy number gain and loss, respectively) revealed six genomic subtypes, termed: 17q12, basal-complex, luminal-simple, luminal-complex, amplifier and mixed subtype. Four of them had striking similarity to intrinsic gene expression subtypes and showed association to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having better prognosis while the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene expression subtypes, the former being enriched for 8p12-amplified cases while the mixed subtype included many tumors with predominantly DNA copy number losses and poor prognosis. Genomic profiling of 359 breast tumors using tiling BAC aCGH. A number of cases were hybridized as replicates or replicate as dye-swaps. Gene expression profiling of 359 breast tumors using 55K oligonucleotide microarrays.

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A New Breast Tumor Intrinsic Gene List Identifies Novel Characteristics that are Conserved Across Microarray Platforms

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