A 22q11.2 amplification in the region encoding microRNA-650 correlates with the epithelial to mesenchymal transition in breast cancer primary cultures of Mexican patients

Abstract

Breast cancer ranks first in incidence and mortality in working age women. Cancer initiation and progression relies on accumulation of genetic and epigenetic aberrations that alter cellular processes, among them, epithelial to mesenchymal transition (EMT) denotes particularly aggressive neoplasias given its capacity to invade and metastasize. Several microRNAs (miRNA) have been found able to regulate gene expression at the core of EMT. In this study, the Affymetrix CytoScan HD array was used to analyze three different primary tumor cell isolates from Mexican breast cancer patients. We found an amplification in band 22q11.2 shared by the three samples, in the region that encodes miRNA-650. Overexpression of this miRNA has been associated with downregulation of tumor suppressors ING4 and NDRG2, which have been implicated in cancer progression. Using the Pathway Linker platform the ING4 and NDRG2 interaction networks showed a significant association with signaling pathways commonly deregulated in cancer. Also, several studies support their participation in the EMT. Supporting the latter, we found that the three primary isolates were E-cadherin negative, vimentin positive, presented a cancer stem cell-like phenotype CD44+CD24−/low and were invasive in Transwell invasion assays. This evidence suggests that the gain of region 22q11.2 contributes to trigger EMT. This is the first evidence linking miR-650 and breast cancer.

A Bioinformatic Pipeline Places STAT5A as a miR-650 Target in Poorly Differentiated Aggressive Breast Cancer

“…Based on our previous findings on Mexican BRCA samples with a common Amp-650 [ 12 ], we considered that this alteration may be enriched in Hispanic population, however, there was no statistical difference in Amp-650 frequencies between Hispanic (10.26%) and non-Hispanic populations (12.7%) ( Figure 1 a). Additionally, since we had observed a correlation between Amp-650 and EMT features, we thought that Amp-650 should be enriched in BRCA subtypes with known poor clinical outcomes and increased mesenchymal markers.…”

“…We previously observed Amp-650 in BRCA samples derived from Mexican patients with mesenchymal/invasive tumors [ 12 ]. Here, we explored public databases to assess whether Amp-650 was a recurrent event in BRCA, and whether we could support an important role specific for aggressive subtypes.…”

“…We previously reported that BRCA samples from Mexican patients had in common an amplification in band 22q11.2 in the region that encodes miR-650 (Amp-650), and this amplification correlated with expression of EMT markers and greater invasive capacity of BRCA cell lines originated from the same patients [ 12 ]. It has been reported that miR-650 works as an oncomirna in hepatocellular carcinoma, colorectal cancer, prostate cancer, and gastric cancer, targeting ING4, NDRG2, and SCARA3 (also known as CSR1) TSG [ 13 , 14 , 15 , 16 ].…”

Clinically relevant morphological structures in breast cancer represent transcriptionally distinct tumor cell populations with varied degrees of epithelial-mesenchymal transition and CD44+CD24- stemness

“…Previous studies described the involvement of miR-650 expression in the poor prognosis of various cancers [ 21 , 22 ]. In BC, the miR-650 amplification has been recently suggested to be involved in triggering EMT [ 23 ].…”

Regulat-INGs in tumors and diseases: Focus on ncRNAs

“…In the latter case, it has been demonstrated that miR-650 confers chemoresistance to docetaxel, an anti-cancerous drug (127). miR-650 can also trigger epithelial to mesenchymal transition in breast cancer by targeting ING4 and NDRG2 (128). Furthermore, several other miRNAs are able to inhibit ING4 expression in cancers.…”