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Abstract
MicroRNAs are critical regulators of gene networks in normal and abnormal biological processes. Focusing on invasive ductal breast cancer (IDC), we have found dysregulated expression in tumor samples of several microRNAs, including the miR-200 family, along progression from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b and miR-7 in IDC patients with regional or distant metastases relative to patients with primary node-negative tumors. Forced expression of miR-200s in MCF10CA1h mammary cells induced an enhanced epithelial program, aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization in vivo. MiR-200s also induced the constitutive activation of the PI3K-Akt signaling through downregulation of PTEN, and the enhanced mammosphere growth and ALDH activity induced in MCF10CA1h cells by miR-200s required the activation of this signaling pathway. Interestingly, the morphology of tumors formed in vivo by cells expressing miR-200s was reminiscent of metaplastic breast cancer (MBC). Indeed, the epithelial components of MBC samples expressed significantly higher levels of miR-200s than their mesenchymal components and displayed a marker profile compatible with luminal progenitor cells. We propose that microRNAs of the miR-200 family promote traits of highly proliferative breast luminal progenitor cells, thereby exacerbating the growth and metastatic properties of transformed mammary epithelial cells.
Highlights
The acquisition of metastatic properties by cancer cells requires both the occurrence of genetic events that confer a minority of neoplastic cells with inherent selfrenewal properties that no longer rely on environmental cues specific to the tissue of origin and the epigenetic remodeling of selected properties that allow the cells to overcome environmental hurdles to metastasis [1]
A miRNA microarray expression screening was performed using tissue samples from 8 ductal carcinomas in situ (DCIS), 20 primary invasive breast ductal carcinoma (IDC) without lymph node (LN) involvement (PNM), 20 primary IDC with regional LN involvement (PM), 20 LN metastases matched to the node-positive primary tumors (LNM) and 20 distant metastases (DM) (Supplementary Table 1) and a pool of 10 normal breast epithelial tissues (N)
Another set of miRNAs, including miR-181a, miR-181b, miR- 210 or miR-7 was upregulated in DM relative to primary tumors (Figure 1A). qPCR confirmed that miR-200b, miR-7 and miR-210 are significantly upregulated from PNM to primary cases and tumors (PM), while miR7, miR-210, miR-181a and miR-181b were up-regulated in DM relative to node-negative tumors (Figure 1B)
Summary
The acquisition of metastatic properties by cancer cells requires both the occurrence of genetic events that confer a minority of neoplastic cells with inherent selfrenewal properties that no longer rely on environmental cues specific to the tissue of origin and the epigenetic remodeling of selected properties that allow the cells to overcome environmental hurdles to metastasis [1]. We have assessed the role of microRNAs in regulating the ability of invasive breast ductal carcinoma (IDC) cells to metastasize to local lymph nodes as a surrogate marker of metastatic potential. We report that the miR-200 family members are significantly upregulated in lymph node (LN) metastases and, by using the MCF10CA1 mammary cell model, that miR-200s induce features of mammary luminal progenitor cells, which may explain the association of enhanced selfrenewal, tumorigenesis and metastatic potentials with high levels of expression of miR-200s
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