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Receptor Biology and Signal Transduction

ORF48-06 - Progesterone Receptor Reprogramming and Coregulator Recruitment Drive the Transcriptional Landscape of Paclitaxel Resistance in ER+ Breast Cancer Cells

Monday, June 15, 2026
2:30 PM - 2:45 PM CT
Location: Room W183A
Disclosure(s):
Carol A. Lange, PhD: No financial relationships to disclose
Julie H. Ostrander, PhD: No financial relationships to disclose



Background: Therapy resistance is a major clinical challenge in ER+ breast cancer. Nuclear receptor (NR) coregulators PELP1 and SRC-3 exhibit nuclear and cytoplasmic functions that promote endocrine/chemotherapy resistance and breast cancer stem-like cell (CSC) phenotypes. We previously demonstrated that PELP1/SRC-3 cytoplasmic and nuclear complexes are enriched in therapy-resistant ER+ breast cancer. Here, we investigate how PELP1, SRC-3, and NR signaling (ER/PR) cooperate to drive paclitaxel resistance (TaxR).

Methods: We utilized a TaxR MCF7 model enriched for CSCs. The mouse mammary intraductal (MIND) model was used to assess in vivo tumor growth and metastasis. We integrated RNA-seq, ATAC-seq, and CUT&RUN (targeting PELP1, SRC-3, and PR) to characterize the epigenomic landscape. Phenotypic validation was performed using tumorsphere assays and siRNA-mediated knockdown.

Results: In vivo studies using the MIND model showed that while TaxR xenografts do not increase primary tumor burden, whereas mice injected with TaxR cells exhibited increased circulating tumor cells, indicative of higher metastatic potential. RNA-seq of TaxR CSC-enriched tumorspheres revealed upregulation of genes associated with paclitaxel resistance (e.g., ABC transporters, tubulins, Hippo signaling). We identified a 20-gene signature associated with decreased recurrence-free and overall survival in clinical datasets using KM Plotter. Comparison with cytoplasmic PELP1 models identified 114 overlapping genes linked to NR signaling, inflammatory response, and EMT.

CUT&RUN analysis demonstrated a marked enrichment of overlapping PELP1/SRC-3 peaks in TaxR cells associated with Notch and TGF beta signaling. Interestingly, PR CUT&RUN suggested that PR genomic reprogramming occurs independently of the PELP1/SRC-3 complex and was enriched for STAT1/3/5 motifs. RPPA and mass cytometry analysis confirmed upregulation of PR and STAT3 in TaxR cells. Functional assays showed that both PR and STAT3 knockdown significantly inhibited tumorsphere formation, confirming their role in maintaining the CSC population.

Conclusions: Our findings suggest that PELP1 and SRC-3, in coordination with reprogrammed PR and STAT3 signaling, drive the epigenetic landscape of therapy-resistant ER+ breast cancer. This study identifies a critical NR-coregulator axis promoting CSC expansion. Targeting these vulnerabilities offers a potential strategy to overcome therapy resistance and prevent metastasis.