Open AccessFour miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer
Author(s) -
John A. Foekens,
Anieta M. Sieuwerts,
Marcel Smid,
Maxime P. Look,
Vanja de Weerd,
Antonius W. M. Boersma,
Jan G.M. Klijn,
Erik A.C. Wiemer,
John W.M. Martens
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0803304105
Subject(s) - microrna , breast cancer , cancer research , biology , estrogen receptor , lymph node , cancer , tumor progression , triple negative breast cancer , oncology , gene , medicine , immunology , genetics
In this study, we quantified 249 mature micro-RNA (miRNA) transcripts in estrogen receptor-positive (ER+ ) primary breast tumors of patients with lymph node-negative (LNN) disease to identify miRNAs associated with metastatic capability. In addition, the prognostic value of the candidate miRNAs was determined in ER− /LNN breast cancer. Unsupervised analysis in a prescreening set of 38 patients identified three subgroups predominantly driven by three miRNA signatures: an ER-driven luminal B-associated miRNA signature, a stromal miRNA signature, and an overexpressed miRNA cluster located on chromosome 19q23, but these intrinsic miRNA signatures were not associated with tumor aggressiveness. Supervised analysis in the initial subset and subsequent analysis in additional tumors significantly linked four miRNAs (miR-7 ,miR-128a ,miR-210 , andmiR-516–3p ) to ER+ /LNN breast cancer aggressiveness (n = 147) and one miRNA (miR-210 ) to metastatic capability in ER− /LNN breast cancer (n = 114) and in the clinically important triple-negative subgroup (n = 69) (allP < 0.05). Bioinformatic analysis coupledmiR-210 to hypoxia/VEGF signaling,miR-7 andmiR-516–3p to cell cycle progression and chromosomal instability, andmiR-128a to cytokine signaling. In conclusion, our work connects four miRNAs to breast cancer progression and to several distinct biological processes involved therein.