Hsa-miR-375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity

Orsolya Giricz, Paul A. Reynolds, Andrew Ramnauth, Christina Liu, Tao Wang, Lesley Stead, Geoffrey J. Childs, Thomas E. Rohan, Nella Shapiro, Susan A. Fineberg, Paraic A. Kenny, Olivier Loudig

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)108-119
Number of pages12
JournalJournal of Pathology
Volume226
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Lobular Carcinoma
Breast
MicroRNAs
Neoplasms
Epithelium
Phenotype
Breast Carcinoma In Situ
Cadherins
Morphogenesis
Linear Models
Breast Neoplasms
Polymerase Chain Reaction

Keywords

  • acinar morphogenesis
  • lobular carcinoma
  • microRNA

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Hsa-miR-375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity. / Giricz, Orsolya; Reynolds, Paul A.; Ramnauth, Andrew; Liu, Christina; Wang, Tao; Stead, Lesley; Childs, Geoffrey J.; Rohan, Thomas E.; Shapiro, Nella; Fineberg, Susan A.; Kenny, Paraic A.; Loudig, Olivier.

In: Journal of Pathology, Vol. 226, No. 1, 01.2012, p. 108-119.

Research output: Contribution to journalArticle

Giricz, Orsolya ; Reynolds, Paul A. ; Ramnauth, Andrew ; Liu, Christina ; Wang, Tao ; Stead, Lesley ; Childs, Geoffrey J. ; Rohan, Thomas E. ; Shapiro, Nella ; Fineberg, Susan A. ; Kenny, Paraic A. ; Loudig, Olivier. / Hsa-miR-375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity. In: Journal of Pathology. 2012 ; Vol. 226, No. 1. pp. 108-119.
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