{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:36:11Z","timestamp":1776836171075,"version":"3.51.2"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022859","name":"FrontierSI","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022859","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dysregulated microRNAs (miRNAs) are critical contributors to breast cancer biology, yet the functional roles of many remain incompletely understood. miR-99b-5p has been widely characterized as a tumor-suppressive miRNA in numerous cancer types, where its expression is consistently reduced in tumors compared with normal tissues. In contrast, our analyses of breast cancer datasets revealed a unique expression pattern: miR-99b-5p is significantly upregulated in breast tumors, suggesting a context-dependent oncogenic function. In this study, we identified miR-99b-5p as an oncogenic driver in triple-negative breast cancer (TNBC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      TCGA-based expression profiling confirmed its elevated levels in breast tumors. Functional assays demonstrated that downregulation of miR-99b-5p in TNBC cells inhibits proliferation and induces apoptosis, indicating a critical role in sustaining tumor cell survival. To elucidate the molecular mechanisms underlying this activity, we performed AGO2-RNA immunoprecipitation followed by high-throughput sequencing (AGO2-RIP-Seq), enabling unbiased identification of miR-99b-5p-associated transcripts. Pathway enrichment analyses revealed that its direct targets converge on apoptotic regulation, cell-cycle control, and ubiquitin-mediated protein degradation. Mechanistic validation through qRT-PCR, Western blotting, and luciferase assays confirmed that miR-99b-5p modulates the TRAIL-R signaling pathway via DR5 and BAK, attenuating apoptotic signaling.\n                      <jats:italic>In vivo<\/jats:italic>\n                      studies using xenograft models established with MDA-MB-231 cells stably expressing miR-99b-5p knockdown showed marked tumor regression, further supporting its oncogenic role.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, these findings establish miR-99b-5p as a context-specific oncogenic miRNA in breast cancer and a promising therapeutic target, particularly for TNBC, where targeted treatment options remain limited.<\/jats:p>\n                  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