title: Delineating transcriptional networks of prognostic gene signatures refines treatment recommendations for lymph node-negative breast cancer patients.
abstract: The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics after surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. In the present study, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer better than currently used multigene prognostic assays, particularly in estrogen receptor-positive patients. Simultaneous examination of p16(INK4A) expression, which predicts tumours that have bypassed cellular senescence, revealed that intermediate levels of p16(INK4A) correlate with an intact pRB pathway and improved survival. A combination of these master transcriptional regulators and p16(INK4A), termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy. Furthermore, OncoMasTR accurately classifies over 60% of patients as 'low risk', an improvement on existing prognostic assays, which has the potential to reduce overtreatment in early-stage patients. Taken together, the present study provides new insights into the transcriptional regulation of cellular proliferation in breast cancer and provides an opportunity to enhance and streamline methods of predicting breast cancer prognosis.
authors.affiliation: The Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Lanigan
authors.affiliation: The Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Gerard L
authors.initials: GL
authors.lastname: Brien
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
authors.forename: Yue
authors.initials: Y
authors.lastname: Fan
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Madden
authors.affiliation: The Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Jerman
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Maratha
authors.affiliation: The Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Fatima
authors.initials: F
authors.lastname: Aloraifi
authors.affiliation: The Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hokamp
authors.affiliation: The Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Eiseart J
authors.initials: EJ
authors.lastname: Dunne
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lohan
authors.affiliation: Department of Histopathology, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Louise
authors.initials: L
authors.lastname: Flanagan
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Garbe
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Martha R
authors.initials: MR
authors.lastname: Stampfer
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Fridberg
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirstrom
authors.affiliation: Department of Histopathology, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Cecily M
authors.initials: CM
authors.lastname: Quinn
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Loftus
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.affiliation: Department of Histopathology, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: James
authors.initials: J
authors.lastname: Geraghty
authors.affiliation: The Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bracken
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D053263:Gene Regulatory Networks; D019942:Genes, p16; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen
keywords: Master Transcriptional Regulators; OncoMasTR; breast cancer; cellular senescence; proliferation