Exploring the Role of APC in Modulating Chemotherapeutic Response in Triple-Negative Breast Cancer cells
Nair, M. T.; VanKlompenberg, M. K.; Prosperi, J. R.
Show abstract
Triple-negative breast cancer (TNBC) lacks targeted therapies and often develops chemoresistance. Since loss of the tumor suppressor APC is common in TNBC, we investigated how APC depletion alters transcriptional adaptation to chemotherapy using RNA-seq profiling of MDA-MB-157 cells and APC knockdown derivatives under control, cisplatin, and paclitaxel treatment. Pathway analyses of the transcriptomes showed that APC knockdown induces extensive remodeling of DNA-damage response, mitochondrial metabolism, inflammatory signaling, and chromatin accessibility, establishing stress-adapted transcriptional states aligned with paclitaxel tolerance (APC_shRNA1) or cisplatin resilience (APC_shRNA2). Machine-learning feature selection (Random Forest + PLS-DA) identified a 43-gene discriminant signature enriched for regulators of cell cycle and DNA repair (CCNB3, ORC1, E2F2, UNG), cytokine signaling (CXCL2, IL11), and metabolic support. These findings suggest that APC loss primes TNBC cells for chemotherapy persistence through an energetically reinforced, transcriptionally flexible survival program, highlighting DDR-OXPHOS-translation and inflammatory circuits as potential therapeutic vulnerabilities.
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