P3-03-08: microRNAs in Mammary Stem-Like Cells and Triple-Negative Breast Cancer; Conserved Functions and Treatment Potential.

Abstract

Abstract Background: Mammary stem and progenitor cells are thought to be precursors of different subclasses of breast cancer. Triple-negative breast cancer exhibit similarities to stem or progenitor-like cells. microRNAs (miRNAs) play pivotal roles in both stem cell biology and oncogenesis. Given their potential as therapeutic targets, little is known, however, regarding miRNAs expression and functions in normal and breast cancer cells. Our objective was to identify which miRNAs are involved in mammary stem cell maintenance and differentiation and study their potential roles in triple-negative breast cancer. We investigated their expression during induced differentiation of mammary stem-like cells, correlated their expression to that of triple-negative breast cancer cells and studied the functions of the most regulated and conserved candidates. Material and Methods: Using large-scale profiling and extensive qPCR confirmation we defined miRNAs regulated during stem-like cell differentiation. We investigated their expression in different breast cancer cell lines, and performed functional studies using miRNA mimics and inhibitors in normal stem-like cells and triple-negative breast cancer cells. Results: Twenty-one miRNAs were strongly regulated in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only 4 miRNAs, including the oncomiR, miR-17, were upregulated in the stem cell-like stage. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways regulated during this transition, including stem cell maintenance, proliferation and differentiation. The cell model used exhibited gene expression profiles resembling basal-like poor prognosis breast cancer. Morover, we present data of miRNAs that target the genes and networks responsible for this correlation. miRNAs detected in this study can also differentiate between human non-cancer and breast cancer cell lines, and a subclass of miRNAs, was specifically downregulated in a basal-like breast cancer cell line. The functions of five miRNAs (miR-200a, -200b, -146b, -148a and -206) were further investigated. Discussion: Our findings suggest that the identified miRNAs have significant roles in biological pathways and networks associated with mammary stem/progenitor cell maintenance and triple-negative breast cancer and support their further evaluation as potential prognostic markers and therapeutic targets in the treatment of breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-03-08.