SUN-210 The role of transcriptional reprogramming and genomic alterations in the transition from chemo-sensitive to chemoresistant triple-negative breast cancer

Abstract Disclosure: S. Gadad: None. M. Sedano: None. Triple-negative breast cancer (TNBC) accounts for approximately 12-20% of all new breast cancer cases diagnosed annually and is known to be associated with poorer clinical outcomes compared to other molecular subtypes of breast cancer. Patients with TNBC typically present with larger tumors and higher tumor grades, resulting in decreased overall and recurrence-free survival rates compared to individuals with non-TNBC tumors. The strategies involved in treating TNBC include chemotherapy agents such as doxorubicin, an anthracycline chemotherapeutic agent; however, its efficacy may vary due to the development of resistance. The specific mechanisms behind the constantly evolving resistance of TNBC to chemotherapy remain unclear, emphasizing the need for further investigation. In our study, we utilized two TNBC cell lines engineered with gradually increasing concentrations of doxorubicin to develop resistance. We conducted integrative genomic analyses to uncover the cellular mechanisms involved, identified altered molecular pathways relevant to cancer, and ascertained the factors contributing to the phenotypic characteristics of doxorubicin-resistant TNBC. Our findings indicate that many evolutionarily young transcripts with coding or limited coding potential are differentially expressed compared to non-resistant TNBC cells. Furthermore, analyses of adjacent genomic regions containing aberrantly expressed genes revealed that these genes are located in areas implicated in cellular plasticity, allowing cancer cells to adapt to the presence of doxorubicin, potentially through transcriptional reprogramming. We are also investigating the genetic and epigenetic alterations that may have facilitated the evolution of TNBC cells into doxorubicin-resistant variants. Additionally, we are assessing the clinical implications of the identified factors by studying them in vivo using mouse models with genetically engineered chemo-sensitive and -resistant cells, linking the outcomes to changes observed in patient samples associated with clinical prognosis. By elucidating the specific mechanisms contributing to the development of doxorubicin resistance in TNBC, we aim to uncover the underlying processes driving resistance and recurrence, potentially paving the way for novel therapeutic strategies. S.S.G. is a CPRIT Scholar in Cancer Research. S.S.G. was supported by a First-time faculty recruitment award from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020). S.S.G. is supported by the The American Cancer Society (RSG-22-170-01-RMC), NIH 1R16GM149497 grants and CPRIT-TREC (RP230420). Presentation: Sunday, July 13, 2025