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Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα– breast cancer

Liu, Jeff C., Voisin, Veronique, Bader, Gary D., Deng, Tao, Pusztai, Lajos, Symmans, William Fraser, Esteva, Francisco J., Egan, Sean E., Zacksenhaus, Eldad
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.15 pp. 5832-5837
breast neoplasms, chemotherapy, drugs, epidermal growth factor, gene expression regulation, genes, humans, immune response, lymph, mice, patients, risk
Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer (BC) is a highly aggressive disease commonly treated with chemotherapy and anti-HER2 drugs, including trastuzumab. There is currently no way to predict which HER2+ BC patients will benefit from these treatments. Previous prognostic signatures for HER2+ BC were developed irrespective of the subtype or the hierarchical organization of cancer in which only a fraction of cells, tumor-initiating cells (TICs), can sustain tumor growth. Here, we used serial dilution and single-cell transplantation assays to identify MMTV-Her2/Neu mouse mammary TICs as CD24+:JAG1– at a frequency of 2–4.5%. A 17-gene Her2-TIC-enriched signature (HTICS), generated on the basis of differentially expressed genes in TIC versus non-TIC fractions and trained on one HER2+ BC cohort, predicted clinical outcome on multiple independent HER2+ cohorts. HTICS included up-regulated genes involved in S/G2/M transition and down-regulated genes involved in immune response. Its prognostic power was independent of other predictors, stratified lymph node+ HER2+ BC into low and high-risk subgroups, and was specific for HER2+:estrogen receptor alpha-negative (ERα–) patients (10-y overall survival of 83.6% for HTICS– and 24.0% for HTICS+ tumors; hazard ratio = 5.57; P = 0.002). Whereas HTICS was specific to HER2+:ERα– tumors, a previously reported stroma-derived signature was predictive for HER2+:ERα+ BC. Retrospective analyses revealed that patients with HTICS+ HER2+:ERα– tumors resisted chemotherapy but responded to chemotherapy plus trastuzumab. HTICS is, therefore, a powerful prognostic signature for HER2+:ERα– BC that can be used to identify high risk patients that would benefit from anti-HER2 therapy.