Triple‐negative breast cancer (TNBC) accounts for 15–25% of diagnosed breast cancers, and its lack of a clinically defined therapeutic target has caused patients to suffer from earlier relapse and higher mortality rates than patients with other breast cancer subtypes. MicroRNAs (miRNAs) are small non‐coding RNAs that regulate the expression of multiple genes through RNA interference to maintain normal tissue function. The tumor suppressor miR‐34a is downregulated in TNBC, and its loss‐of‐expression correlates with worse disease outcomes. Therefore, delivering miR‐34a mimics into TNBC cells is a promising strategy to combat disease progression. To achieve this goal, we synthesized layer‐by‐layer assembled nanoparticles (LbL NPs) comprised of spherical poly(lactic‐co‐glycolic acid) cores surrounded by alternating layers of poly‐L‐lysine (PLL) and miR‐34a. TNBC cells internalized these LbL NPs to a greater extent than polyplexes comprised of PLL and miRNA, and confocal microscopy showed that LbL NPs delivered a substantial fraction of miR‐34a cargo into the cytosol. This yielded robust suppression of the miR‐34a target genes CCND‐1, Notch‐1, Bcl‐2, Survivin, and MDR‐1, which reduced TNBC cell proliferation and induced cell cycle arrest. These data validate that miR‐34a delivery can impair TNBC cell function and support continued investigation of this platform for treatment of TNBC.
Chaperonin-containing TCP-1 (CCT or TRiC) is a multi-subunit complex that folds many of the proteins essential for cancer development. CCT is expressed in diverse cancers and could be an ideal therapeutic target if not for the fact that the complex is encoded by eight distinct genes, complicating the development of inhibitors. Few definitive studies addressed the role of specific subunits in promoting the chaperonin’s function in cancer. To this end, we investigated the activity of CCT2 (CCTβ) by overexpressing or depleting the subunit in breast epithelial and breast cancer cells. We found that increasing total CCT2 in cells by 1.3-1.8-fold using a lentiviral system, also caused CCT3, CCT4, and CCT5 levels to increase. Likewise, silencing
- Award ID(s):
- 1755761
- NSF-PAR ID:
- 10153981
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 10
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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