Abstract
Hyperactivation of ERK1/2 MAPK (hMAPK) leads to loss of estrogen receptor (ER) expression and poor outcome in breast cancer. microRNAs (miRNA) play important regulatory roles and serve as biomarkers of disease. Here, we describe molecular, pathologic, and clinical outcome associations of an hMAPK-miRNA expression signature in breast cancer. An hMAPK-miRNA signature was identified, and associations of this signature with molecular and genetic alterations, gene expression, pathologic features, and clinical outcomes were determined in primary breast cancers from training data and validated using independent datasets. Univariate and multivariate analyses identified subsignatures associated with increased disease recurrence and poorer disease survival among ER-positive (ER(+)) patients, respectively. High-hMAPK-miRNA status significantly correlated with ER-negativity, enrichment for basal and HER2-subtypes, and reduced recurrence-free and disease-specific survival in publicly available datasets. A robust determination of a recurrence signature and a survival signature identified hMAPK-miRNAs commonly associated with poor clinical outcome, and specific subsets associated more closely with either disease recurrence or disease survival, especially among ER(+) cancers of both luminal A and luminal B subtypes. Multivariate analyses indicated that these recurrence and survival signatures significantly associated with increased risk of disease-specific death and disease recurrence in ER(+) cancer and ER(+) cancers treated with hormone therapy. We report an hMAPK-miRNA signature and two subsignatures derived from it that associate significantly with adverse clinical features, poor clinical outcome, and poor response to hormone therapy in breast cancer, thus identifying potential effectors of MAPK signaling, and novel predictive and prognostic biomarkers or therapeutic targets in breast cancer.
Highlights
Treatment decisions in breast cancer are informed by tumor grade, stage, and lymph node status, and by genomic biomarkers, estrogen receptor (ER), and HER2
We confirmed that the Hyperactivation of ERK1/2 MAPK (hMAPK)– mRNA signature was represented in the primary breast tumor datasets with paired mRNA–miRNA expression data analyzed in this study [The Cancer Genome Atlas (TCGA): "TCGA"; GEO GSE22220: "Buffa dataset"; GEO GSE19536: "Enerly dataset"; METABRIC miRNA dataset: "METABRIC"; datasets previously described [22, 31, 32, 34, 35]; clinical characteristics in Supplementary Table S1]
Primary breast cancers from training and validation datasets were classified as "high-hMAPK– miRNA" or "low-hMAPK–miRNA" according to this miRNA signature. To confirm that this hMAPK–miRNA signature identifies tumors with activated ERK1/2–MAPK signaling, we analyzed the expression of several genes regulated by ERK1/2 in breast cancer in the TCGA training cohort
Summary
Treatment decisions in breast cancer are informed by tumor grade, stage, and lymph node status, and by genomic biomarkers, estrogen receptor (ER), and HER2. Multigene assays such as Oncotype DX and Mammaprint are being used in prognostic capacities for patients with breast cancer [1, 2]. Prominent roles for PI3K–AKT–MTOR signaling in the biology of breast cancer have been established, in particular downstream of HER2 (ERBB2: gene product: HER2 protein product) signaling and in tamoxifen resistance mechanisms [9,10,11]
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