title: BRCA1 regulation of epidermal growth factor receptor (EGFR) expression in human breast cancer cells involves microRNA-146a and is critical for its tumor suppressor function.
abstract: Breast cancer 1 (BRCA1)-associated breast cancers are mostly basal-like high-grade ductal carcinomas that frequently overexpress epidermal growth factor receptor (EGFR). Aberrant EGFR expression is correlated with disease progression, resistance to radiation and chemotherapy, and poor clinical prognosis. Although BRCA1 is involved in multiple cellular processes, its functional role in EGFR regulation remains enigmatic. Here, we report a previously unrecognized posttranscriptional mechanism by which BRCA1 regulates EGFR expression through the induction of miR-146a. We demonstrate that EGFR expression correlates negatively with BRCA1, whereas miR-146a levels increase with BRCA1. We show that BRCA1 binds to MIR146A promoter and activates transcription, which in turn attenuates EGFR expression. Knockdown of miR-146a in BRCA1-overexpressing cells negated this effect and suppressed its ability to inhibit proliferation and transformation. In archived triple-negative breast cancer samples, we show a strong positive correlation between BRCA1 and miR-146a expression. We also show that low expression of miR-146a strongly predicts positive lymph node status and is associated with distinctively poor overall survival of patients. Together, these observations provide an insight into a novel BRCA1miR-146aEGFR paradigm by which BRCA1 carries out an aspect of tumor suppressor function that is potentially amenable to therapeutic intervention.
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA [2] The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kumaraswamy
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Wendt
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Augustine
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Stecklein
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Sibala
authors.affiliation: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: 1] Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA [2] Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gunewardena
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA [2] The University of Kansas Cancer Center, Kansas City, KS, USA [3] Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA [4] Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA [5] Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Jensen
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors