Implication of an exosome-based gene signature for estimating clinical outcomes of triple-negative breast cancer and assisting in individualized therapy

Exosomes play a crucial role in triple-negative breast cancer (TNBC), influencing various aspects of tumor progression. Given the importance of exosomes in TNBC biology, we proposed a novel exosome-based model that was critically implicated in TNBC. Bulk and single-cell transcriptomics and genetic mutations of TNBC patients were curated for our study. Characteristic exosome genes were selected via LASSO analysis, with subsequent construction of an exosome-based model. The effectiveness in estimating clinical outcomes and treatment responses was then evaluated and validated. MDA-MB-231 and MDA-MB-468 TNBC cells were transiently transfected with FAM129B siRNAs, and cell proliferation and migration were measured via EdU and wound healing assays. The study determined 7 characteristic exosome genes for TNBC: ALCAM, FAM129B, GNB2, KRT6A, PGK1, SERPINE1, and THY1, which were utilized for defining the exosome-based gene signature. It was proven that the signature accurately estimated patient prognosis, and functioned as an independent prognostic predictor. High-risk tumors owned shorter overall survival time, but were suitable for treatment with docetaxel and several small-molecule agents (MK-0752, BRD-K33199242, IC-87114, fumonisin B1, ilomastat, GW-788388, afobazole, and batimastat). High- and low-risk tumors presented the distinct genetic mutation characteristics. The characteristic exosome genes were specifically expressed in the TNBC microenvironment components, indicating their involvement in modulating the microenvironment. High-risk individuals were inferred to better respond to immune checkpoint blockade (CD276, NRP1, TNFRSF4, TNFSF4 or CTLA4). Experimentally, inhibition of FAM129B effectively attenuated proliferative and aggressive phenotypes of TNBC cells. Collectively, our findings proposed the exosome-based gene signature for accurate estimation of clinical outcomes and assisting in individually tailoring therapies in TNBC as well as discovered FAM129B as a potential therapeutic target.