title: Hsa-miR-375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity.
abstract: Invasive lobular carcinoma (ILC) of the breast, characterized by loss of E-cadherin expression, accounts for 5-15% of invasive breast cancers and it is believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15-20% risk of progression to ILC over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina miRNA profiling platform, designed for simultaneous analysis of 470 mature miRNAs, we analysed the profiles of archived normal breast epithelium, LCIS lesions found alone, LCIS lesions concurrent with ILC, and the concurrent ILCs as a model of linear histological progression towards ILC. We identified two sets of differentially expressed miRNAs, the first set highly expressed in normal epithelium, including hsa-miR-224, -139, -10b, -450, 140, and -365, and the second set up-regulated during lobular neoplasia progression, including hsa-miR-375, -203, -425-5p, -183, -565, and -182. Using quantitative RT-PCR, we validated a trend of increasing expression for hsa-miR-375, hsa-miR-182, and hsa-miR-183 correlating with ILC progression. As we detected increased expression of hsa-miR-375 in LCIS lesions synchronous with ILC, we sought to determine whether hsa-miR-375 might induce phenotypes reminiscent of lobular neoplasia by expressing it in the MCF-10A 3D culture model of mammary acinar morphogenesis. Increased expression of hsa-miR-375 resulted in loss of cellular organization and acquisition of a hyperplastic phenotype. These data suggest that dysregulated miRNA expression contributes to lobular neoplastic progression.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Orsi
authors.initials: O
authors.lastname: Giricz
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reynolds
authors.forename: Andrew
authors.initials: A
authors.lastname: Ramnauth
authors.forename: Christina
authors.initials: C
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Lesley
authors.initials: L
authors.lastname: Stead
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Childs
authors.forename: Thomas
authors.initials: T
authors.lastname: Rohan
authors.forename: Nella
authors.initials: N
authors.lastname: Shapiro
authors.forename: Susan
authors.initials: S
authors.lastname: Fineberg
authors.forename: Paraic A
authors.initials: PA
authors.lastname: Kenny
authors.forename: Olivier
authors.initials: O
authors.lastname: Loudig
mesh_terms: D061354:Acinar Cells / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000473:pathology; D016764:Cell Polarity / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D042282:Microdissection; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA
chemical_list: C540933:MIRN375 microRNA, human; D035683:MicroRNAs