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.

Tumour‐suppressive microRNA‐224 inhibits cancer cell migration and invasion via targeting oncogenic TPD52 in prostate cancer

“…These results strongly suggested that miR-224 functioned as a tumour suppressor in PCa cells. Downregulation of miR-224 has also been reported in other types of human cancers, including ovarian, lung, and breast cancers, in addition to PCa [17][18][19][20][21]. Additionally, one study has shown that more aggressive PCa is associated with lower expression of miR-224 and that downregulation of miR-224 is associated with biochemical relapse [22].…”

“…Improved understanding of ncRNAs is necessary for continued progress in cancer research. MicroRNAs (miRNAs) are endogenous small ncRNA molecules (19)(20)(21)(22) bases in length) that regulate the expression of protein-coding genes by repressing translation or cleaving RNA transcripts in a sequencespecific manner [5]. A significant amount of evidence suggests that miRNAs are aberrantly expressed in many human cancers and play significant roles in the initiation, development, and metastasis of those cancers [6].…”

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

“…16,17,[23][24][25][26][27][28][29][30][31][39][40][41][42] Downregulation of miR-375 has been reported for gastric cancer, cervical cancer, pancreatic ductal adenocarcinoma and hepatocellular carcinoma. 26,27,29,30,[43][44][45] In gastric cancer, ectopic expression of miR-375 in cancer cells reduced cell viability and induced apoptosis by targeting PDK1 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein z (YWHAZ).…”

“…41 miRNA expression profiling in invasive lobular carcinoma of the breast showed that miR-375 was upregulated when compared with normal breast epithelium. 40 Ectopic expression of miR-375 in non-tumorigenic breast epithelial MCF-10 A cells induced loss of cellular organization and a hyperplastic phenotype. 40 In prostate cancer (PC), both deep sequencing and microarray analysis of miRNA expression revealed that miR-375 was significantly upregulated in tumor tissues.…”

“…40 Ectopic expression of miR-375 in non-tumorigenic breast epithelial MCF-10 A cells induced loss of cellular organization and a hyperplastic phenotype. 40 In prostate cancer (PC), both deep sequencing and microarray analysis of miRNA expression revealed that miR-375 was significantly upregulated in tumor tissues. 46 Serum levels of miR-375 in PC patients are upregulated compared with those of healthy Functional significance of miR-375 in human cancer T Kinoshita et al controls.…”