Re-expression of miR-200c suppresses proliferation, colony formation andin vivotumor growth of murine claudin-low mammary tumor cells

Abstract

Claudin-low breast cancer is a relatively rare breast cancer subtype. These cancers are typically ER−/PR−/HER2− and express high levels of mesenchymal genes as well as genes associated with inflammation, angiogenesis and stem cell function. In addition to alterations in gene expression, it was recently demonstrated that claudin-low breast cancers express very low levels of the miR-200 family of miRNAs. Given that each miRNA can regulate tens, hundreds or even thousands of genes, miRNAs are being evaluated as therapeutic targets. In this study we show that mammary tumors from MTB-IGFIR transgenic mice and cell lines derived from these tumors represent a model of human claudin-low breast cancer and murine claudin-low mammary tumors and cell lines express only very low levels of all five members of the miR-200 family. Reduced miR-200 family expression appears to be regulated via methylation as cells and tumors expressing low levels of miR-200 family members had higher levels of CpG methylation in a putative promoter region than tumors and cells expressing high levels of miR-200 family members. Re-expression of miR-200c in murine claudin-low mammary tumor cells inhibited tumor cell proliferation and colony formation in vitro and tumor growth in vivo. With respect to tumor growth in vivo, re-expression of miR-200c was associated with a reduction in tumor vasculature and expression of Flt1 and Vegfc. Therefore, miR-200c is an important regulator of mesenchymal tumor cell growth.

Integrative analysis of copy number and gene expression data identifies potential oncogenic drivers that promote mammary tumor recurrence

“…we have previously shown that the miR-200c is downregulated in RSTs. 37 We have also observed a correlation between copy number loss of Cdkn2a and platelet-derived growth factor receptor α and β In extending our findings to human breast cancer, we found high MET and YAP1 mRNA levels were associated with a reduction in RFS in basal-like breast cancer patients. These data are in line with previous studies linking these genes with the basal-like subtype.…”

“…In mammary epithelial cells, loss of p53 leads to downregulation of miR‐200c expression which is followed by activation of the EMT program via upregulation of the transcriptional regulator Zeb1 . Indeed, we have previously shown that the miR‐200c is downregulated in RSTs . We have also observed a correlation between copy number loss of Cdkn2a and platelet‐derived growth factor receptor α and β (PDGFR α/β) protein expression in RSTs (unpublished data).…”

Recent progress on the effects of microRNAs and natural products on tumor epithelial–mesenchymal transition

“…Re-expression of miR-200c in vitro did not change the expression of ZEB1/2 significantly. Invasion chamber assay showed little diminishment in tumor cell invasion either 20. What is more, another study has shown that miR-141/200 re-expression increased the ability to invade and migrate in human CLBC cell line MDA-MB-231.…”

“…The exogenous expression of P53 gene could reverse the TGF-β-induced EMT 19. This study links the most important genetic alteration in human cancer to the emerging fields of EMT and cancer stem cells, which are of importance for metastasis 20. In ovarian cancer cells, the luciferase reporter assay revealed that mutations in P53 binding region in the miR-200b/a/429 and miR-200c/141 promoters reduced luciferase activity by 40% ( P <0.003, t -test) 21.…”

MicroRNAs in neuroblastoma differentiation and differentiation therapy

“…The therapeutic potential of miRNA-based agents has been investigated in in vivo models of many types of cancers [68][69][70][71][72][73][74] . Systemic delivery methods, such as encapsulation of miRNAs in nanoparticles or chemical modification of miRNAs, could be an effective technique for personalized therapies and cancer treatments [68] .…”