Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking targeted therapy options. Novel therapies which also target chemotherapy-resistant cancer stem cells (CSCs) within tumors would lead to improved outcomes for TNBC patients. Breast CSCs can be defined by increased aldehyde dehydrogenase (ALDH) enzymatic activity. Recent evidence suggests that long non-coding RNAs (lncRNAs) contribute to CSC maintenance and are potential novel therapeutic targets.
To discover novel therapeutic targets for TNBC and CSCs we screened lncRNAs that are most enriched in TNBCs and breast CSCs for oncogenic activity. We used quantitative polymerase chain reaction (QPCR), cellular fractionization, flow cytometry, antisense oligonucleotides and mammosphere formation assays to assess lncRNA function and targetability in TNBC cell lines and a patient-derived xenograft.
We identified prostate androgen regulated transcript 1(PART1) as enriched in both TNBCs and CSCs. PART1 is also associated with worse patient outcomes among basal-like breast cancer patients. Knockdown of PART1 decreased cell proliferation of TNBC cell lines HCC1806 and HCC1395, and reduced tumor growth of HCC1806 cells. Cellular fractionization revealed that PART1 is predominately located in the cytoplasm, consistent with potential function as a miRNA sponge. Targeting PART1 with antisense oligonucleotides in a PDX and in the HCC1806 cell line resulted in a decrease in mammosphere forming potential. This suggests that PART1 may contribute to CSC maintenance and could be targeted to reduce CSC numbers in tumors.
PART1 is of interest as a novel therapeutic target for TNBCs and CSCs. Further analysis will focus on investigating its potential function as a miRNA sponge in breast cancer.
The authors.
Canadian Institutes of Health Research Dalhousie University (Killam Award) Cancer Research Trainee Program.
All authors have declared no conflicts of interest.