Abstract 1425: Transcriptional and epigenomic landscape of paclitaxel resistant MCF-7 cells

PELP1 and SRC-3 function as essential coregulatory proteins in normal development and cancer. Overexpression of SRC-3 and PELP1 independently influence cancer cell biology through the regulation of 1) proliferation; 2) apoptosis and autophagy; 3) migration, invasion, and metastasis; and 4) therapy resistance. PELP1 and SRC-3 have both nuclear and cytoplasmic functions, and prior reports indicate that cytoplasmic localization of SRC-3 is necessary for SRC-3 phosphorylation that impacts the transcriptional coregulatory function of SRC-3. Cytoplasmic localization of PELP1 promotes tamoxifen and paclitaxel resistance, and breast cancer stem-like cell (CSC) phenotypes. We previously showed that cytoplasmic and nuclear PELP1/SRC-3 complexes are enriched in ER+ therapy resistant breast cancer. Our published data suggests that altered PELP1/SRC-3 signaling leads to altered gene expression that contributes to the expansion of breast CSC population in therapy resistant ER+ breast cancer. To better understand the transcription and epigenomic landscape of this therapy resistant model, we used a combination of RNA-seq and CUT&RUN. Genes previously shown to be associated with paclitaxel resistance were found upregulated in MCF7 TaxR CSC-enriched tumorspheres (i.e. ABCB1, TUBB2B), with ABCB1 being the most differentially expressed gene compared to parental MCF7 cells. RNA-seq analysis suggests that an upregulation of genes involved in interferon and inflammatory response, as well and Ras signaling and EMT in TaxR cells. We also identified 114 overlapping genes from our TaxR model and our previously published cytoplasmic PELP1 model. Pathway analysis indicates that these genes are regulated by nuclear receptors (i.e. ER and PR), which is supported by an increase in PR expression in TaxR CSC-enriched 3D cultures. CUT&RUN data indicates an enrichment in PELP1/SRC-3 overlapping peaks in TaxR cells. Genes associated with overlapping peaks are associated with androgen response, cholesterol homeostasis, notch signaling, protein secretion and TGF-beta signaling MSigDB Hallmark pathways. Together these data support our hypothesis that PELP1/SRC-3 complexes are reprogrammed to promote therapy resistances and CSC phenotypes. We aim to use these studies to identify pathways that can be targeted within CSCs to eliminate this quiescent population and prevent breast cancer metastasis. Citation Format: Julie Hanson Ostrander, Thu Truong, Marygrace Trousdell, Kyla Hagen, Nuri Alpay Temiz, Michael Ciccone, Fatemah Iman Dewji, Camila dos Santos, Carol A. Lange. Transcriptional and epigenomic landscape of paclitaxel resistant MCF-7 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1425.