Epithelial and Stromal MicroRNA Signatures of Columnar Cell Hyperplasia Linking Let-7c to Precancerous and Cancerous Breast Cancer Cell Proliferation

Abstract

Columnar cell hyperplasia (CCH) is the earliest histologically identifiable breast lesion linked to cancer progression and is characterized by increased proliferation, decreased apoptosis and elevated oestrogen receptor α (ERα) expression. The mechanisms underlying the initiation of these lesions have not been clarified but might involve early and fundamental changes in cancer progression. MiRNAs are key regulators of several biological processes, acting by influencing the post-transcriptional regulation of numerous targets, thus making miRNAs potential candidates in cancer initiation. Here we have defined novel epithelial as well as stromal miRNA signatures from columnar cell hyperplasia lesions compared to normal terminal duct lobular units by using microdissection and miRNA microarrays. Let-7c were among the identified downregulated epithelial miRNAs and its functions were delineated in unique CCH derived cells and breast cancer cell line MCF-7 suggesting anti-proliferative traits potentially due to effects on Myb and ERα. MiR-132 was upregulated in the stroma surrounding CCH compared to stoma surrounding normal terminal duct lobular units (TDLUs), and overexpression of miR-132 in immortalized fibroblasts and in fibroblasts co-cultured with epithelial CCH cells caused substantial expression changes of genes involved in metabolism, DNA damage and cell motility. The miRNA signatures identified in CCH indicate early changes in the epithelial and stromal compartment of CCH and could represent early key alterations in breast cancer progression that potentially could be targeted in novel prevention or treatment schedules.

MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/β-catenin pathway

“…MicroRNAs (miRNAs) are small non-coding RNAs that regulate target gene expression by binding to the 3′-untranslated region (3′-UTR) of their target mRNAs, resulting in either mRNA degradation or translational repression 6 7 . MiRNAs play essential roles in many normal biological processes, including cell proliferation, apoptosis, differentiation and stress resistance 8 9 . Accumulating evidence has shown that dysregulation of miRNAs expression is associated with oncogenic transformation.…”

Review on the Applications and Molecular Mechanisms ofXihuangPill in Tumor Treatment

“…Furthermore, XH regulated T-lymphocyte subsets and improved the immunity of breast cancer patients taking CEF [ 15 ]. Breast hyperplasia, especially of the columnar cells, is the earliest histologically identifiable lesion linked to cancer progression [ 26 ]. Aside from the tumor, XH can treat benign lesions such as breast hyperplasia and prevent transformation into malignancies [ 27 ].…”

MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation

“…Previous research on let-7c has primarily focused on functions and roles in cancer. It has been shown that let-7c inhibits cancer cell survival by regulating cell proliferation (Bjorner et al, 2014) and apoptosis (Zhan et al, 2013). Recent studies suggest that let-7c is an important regulator of macrophage polarization.…”