Prosperi, J. R. | Search bioRxiv

bioRxiv2026

Exploring the Role of APC in Modulating Chemotherapeutic Response in Triple-Negative Breast Cancer cells

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.

cancer biology↗

bioRxiv2020

Adenomatous Polyposis Coli Loss Controls Cell Cycle Regulators and Response to Paclitaxel

Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in PTX-treated APC shRNA1 cells compared to PTX-treated controls, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.

cancer biology↗