Abstract
Simple SummaryLong non-coding RNAs (lncRNAs) play an important role in cancer progression. Herein we provide new information regarding the role of prostate androgen regulated transcript 1 (PART1). We show that the lncRNA PART1 is enriched in triple-negative breast cancers and cancer stem cell populations. We demonstrate its role in cancer cell and tumor growth and provide evidence for its association with worse survival in a subset of breast cancer patients. Importantly, our genome-wide analyses have revealed novel insights into the function of this lncRNA, demonstrating how it changes the microRNA (miRNA) landscape leading to genome-wide mRNA expression regulation. Our study suggests that PART1 represents an attractive target for the treatment of triple-negative breast cancers.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 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal-like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 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, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR-190a-3p, miR-937-5p, miR-22-5p, miR-30b-3p, and miR-6870-5p. We confirmed the novel interaction between PART1 and miR-937-5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line-specific effects in terms miRNA-PART1 interactions and gene regulation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.
Highlights
Accumulating evidence supports a role for long non-coding RNAs in the development and progression of cancer and response to therapy
In the cell lines prostate androgen regulated transcript 1 (PART1) expression was not enriched in the basal-like/Triple-negative breast cancers (TNBCs) cells (Figure 1C,D) as we had noted in patient tumors (Figure 1A,B)
We wondered if the higher PART1 expression in non-TNBC cell lines is a result of cell culturing conditions
Summary
Accumulating evidence supports a role for long non-coding RNAs (lncRNAs) in the development and progression of cancer and response to therapy. Defined as non-coding transcripts greater than 200 bases in length, the number of lncRNAs identified in humans has surpassed the number of coding genes; the function of only a fraction is known. 1 (MALAT1), and non-coding RNA in the aldehyde dehydrogenase 1A pathway (NRAD1), have all been described as oncogenic and dysregulated in breast cancer [5,6,7]. Hundreds of lncRNAs (most of which are uncharacterized) are upregulated in triple-negative breast cancers (TNBCs) and represent an area of potential discovery in terms of functionally important players in the progression of this subtype [8]
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