LncRNA PART1 Promotes Proliferation and Migration, Is Associated with Cancer Stem Cells, and Alters the miRNA Landscape in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non-coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (<i>PART1</i>) is enriched in TNBCs and in Aldefluor^high CSCs, and is associated with worse outcomes among basal-like breast cancer patients. Although <i>PART1</i> is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of <i>PART1</i> in TNBC cell lines and a patient-derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin-Va, <i>MYO5A</i>; zinc fingers and homeoboxes protein 2, <i>ZHX2</i>). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic <i>PART1</i>, including <i>miR-190a-3p</i>, <i>miR-937-5p</i>, <i>miR-22-5p</i>, <i>miR-30b-3p</i>, and <i>miR-6870-5p</i>. We confirmed the novel interaction between <i>PART1</i> and <i>miR-937-5p</i>. In general, miRNAs altered by <i>PART1</i> were less abundant than <i>PART1</i>, potentially leading to cell line-specific effects in terms miRNA-<i>PART1</i> interactions and gene regulation. Together, the altered miRNA landscape induced by <i>PART1</i> explains most of the protein-coding gene regulation changes (e.g., <i>MYO5A</i>) induced by <i>PART1</i> in TNBC.