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

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 target...

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Bibliographic Details
Published in:Cancers 2021-05, Vol.13 (11), p.2644
Main Authors: Cruickshank, Brianne M., Wasson, Marie-Claire D., Brown, Justin M., Fernando, Wasundara, Venkatesh, Jaganathan, Walker, Olivia L., Morales-Quintanilla, Fiorella, Dahn, Margaret L., Vidovic, Dejan, Dean, Cheryl A., VanIderstine, Carter, Dellaire, Graham, Marcato, Paola
Format: Article
Language:English
Subjects:
Androgens
Apoptosis
Breast cancer
Cancer therapies
Cell growth
Cell migration
Cell proliferation
Cloning
Dehydrogenases
Gene expression
Gene regulation
Genomes
Metastasis
miRNA
Myosin
Non-coding RNA
Patients
Prostate
Prostate cancer
Stem cells
Transcription
Transcriptomes
Tumors
Xenografts
Zinc finger proteins
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13112644