title: A prognostic gene signature for metastasis-free survival of triple negative breast cancer patients.
abstract: Although triple negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, they currently lack targeted therapies. Because this classification still includes a heterogeneous collection of tumors, new tools to classify TNBCs are urgently required in order to improve our prognostic capability for high risk patients and predict response to therapy. We previously defined a gene expression signature, RKIP Pathway Metastasis Signature (RPMS), based upon a metastasis-suppressive signaling pathway initiated by Raf Kinase Inhibitory Protein (RKIP). We have now generated a new BACH1 Pathway Metastasis gene signature (BPMS) that utilizes targets of the metastasis regulator BACH1. Specifically, we substituted experimentally validated target genes to generate a new BACH1 metagene, developed an approach to optimize patient tumor stratification, and reduced the number of signature genes to 30. The BPMS significantly and selectively stratified metastasis-free survival in basal-like and, in particular, TNBC patients. In addition, the BPMS further stratified patients identified as having a good or poor prognosis by other signatures including the Mammaprint® and Oncotype® clinical tests. The BPMS is thus complementary to existing signatures and is a prognostic tool for high risk ER-HER2- patients. We also demonstrate the potential clinical applicability of the BPMS as a single sample predictor. Together, these results reveal the potential of this pathway-based BPMS gene signature to identify high risk TNBC patients that can respond effectively to targeted therapy, and highlight BPMS genes as novel drug targets for therapeutic development.
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Unjin
authors.initials: U
authors.lastname: Lee
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Casey
authors.initials: C
authors.lastname: Frankenberger
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Bevilacqua
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Departments of Statistics, Ecology and Evolution, Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Reinitz
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Marsha Rich
authors.initials: MR
authors.lastname: Rosner
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018572:Disease-Free Survival; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D035683:MicroRNAs; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; C487931:mirnlet7 microRNA, human