Mucin 1 (Muc1) is a secreted, oncogenic mucin that is aberrantly overexpressed in breast cancer cells but its potential role in breast cancers stem cells (BCSCs) have not been explored. Emerging evidence suggests that mucin play important roles in tumor metastasis and drug resistance. MicroRNAs (miRNA), small noncoding RNAs that play critical roles in normal stem cell functions during development, have emerged as important regulators of BCSCs as well.
Muc positive (+)/(-) cells were isolated from patient-derived cancer (n = 25), and normal BC tissues (n = 15) and propagated in nonadhesive suspension cell culture to assess their phenotypic characteristics. Further miRNAs expression profiling was done by using microRNA TaqMan® Low Density Array Cards v2.0 (TLDA cards A, Invitrogen), based on qReal-Time PCR array.
Upon Muc1(+) selection, we have found rare subpopulation of undifferentiated cells expressing Muc1 in 70% BC tissue samples. These cells were growing indefinitely (∼28 weeks) as mammospheres in serum-free cell culture medium and also shown high ALDH activity and Muc1, EpCAM, CD49f, and CD44 + /CD24- expression in comparison to Muc1(-) subpopulations (p < 0.05). Among altered miRNAs, Muc(+) BCSCs were showing significantly downregulated expression of miR-125b as compared to adhered and Muc(-) cell population. In addition downregulated expression of miR-125b in most BCSCs and clinical specimens of BC were noted, and correlated with cellular differentiation and drug resistance potential in BC patients. We afterward demonstrated that miR-125b overexpression attenuated the BCSC's self renewal and proliferation potential along with Muc1, Dicer 1, Prominin1, ELF4EBP1, ALDH4A1, DDR1, KRAS and BCL2 expression, whereas knockdown of miR-125b promoted these.
These findings suggest that ectopic expression of miR-125b provides a promising strategy to inhibit cancer stem cells.
Clinical trial identification
All authors have declared no conflicts of interest.
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