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. 2025 Aug 10:625:217794.
doi: 10.1016/j.canlet.2025.217794. Epub 2025 May 17.

Preferential release of microRNAs via extracellular vesicles is associated with ductal carcinoma in situ to invasive breast cancer progression

Sugantha Priya Elayapillai  1 , Samrita Dogra  2 , Cole Hladik  3 , James Lausen  4 , Matthew Bruns  5 , Amy Gin Gossett  4 , Fariba Behbod  6 , Chao Xu  7 , Roy Zhang  4 , Wei-Qun Ding  8 , Bethany N Hannafon  9
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Preferential release of microRNAs via extracellular vesicles is associated with ductal carcinoma in situ to invasive breast cancer progression

Sugantha Priya Elayapillai et al. Cancer Lett. .

Abstract

Ductal carcinoma in situ (DCIS) is a precancerous condition that increases the risk of invasive breast cancer (IBC), but not all DCIS cases progress to IBC. The molecular factors driving this transition remain unclear. Small extracellular vesicles (sEVs), or exosomes, play a role in advanced cancer progression, though their function in DCIS is poorly understood. This study explores the role of sEVs and their RNA content in DCIS progression. We found that Rab27A, a key regulator of exosome release, is upregulated in DCIS and IBC tissues compared to normal breast tissue. Inhibiting sEV release by knocking down Rab27A disrupted pro-invasive signaling and reduced invasion in a DCIS mouse model. Using the MCF10 breast cancer progression series, we observed increased microRNA (miRNA) content in sEVs as cells transitioned from normal to malignant, with the most significant differential miRNA expression seen in IBC-derived sEVs. In vivo, DCIS progression raised circulating sEV miRNA levels, which were reduced by Rab27A knockdown. Reintroducing miR-205, enriched in IBC-derived sEVs, suppressed DCIS cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) markers. Co-expression of miR-205 with Rab27A knockdown also suppressed TGF-β signaling, activated MAPK p38, and induced cell cycle arrest and apoptosis. These findings show that the RNA cargo of sEVs changes during malignancy, with specific miRNAs driving DCIS progression. Re-expression of miR-205 offers a promising therapeutic approach to prevent DCIS from becoming invasive.

Keywords: Breast cancer; DCIS; Exosomes; Extracellular vesicles; Intraductal model; microRNA.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bethany N. Hannafon reports financial support was provided by the Oklahoma Center for the Advancement of Science and Technology. Bethany N. Hannafon reports financial support was provided by the Oklahoma Tobacco Settlement Endowment Trust. The corresponding author is an Editorial Board Member for Cancer Letters and was not involved in the editorial review or the decision to publish this article. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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