Abstract PS2-11-24: Collagen prolyl 4-hydroxylase promotes breast cancer endocrine resistance via regulation cellular stress

Abstract The luminal subtype accounts for approximately 70% of all diagnosed breast cancers cases. Endocrine therapy is the first-line therapy for luminal breast cancer patients. About 30%-50% of luminal breast cancer patients with five to ten years of treatment acquire resistance to endocrine therapy. Understanding the mechanisms of endocrine resistance and identifying new therapeutic targets remain urgent priorities. Here, we show that expression of the alpha subunit of Prolyl hydroxylation (P4HA1), an enzyme hydroxylates proline into 4-hydroxyproline at the Y position of the collagen -X-Y-Gly- triplet motif, is increased in endocrine therapy resistant luminal breast cancer cells compared with parental endocrine therapy sensitive cells. In luminal breast cancer patients, increased P4HA1 expression significantly correlates with short relapse-free survival. Knockdown of P4HA1 or P4HA1 small molecular inhibitors treatment restores endocrine-resistant luminal breast cancer cells sensitivity to hydroxytamoxifen (4OHT) or fulvestrant treatment, by enhancing cell apoptosis and inhibiting cell proliferation. These results indicate that P4HA1 is an important regulator for endocrine resistance of breast cancer. We also show that the inactivation of P4AH1 combined with endocrine treatment dramatically enhances endoplasmic reticulum (ER) stress-related gene expression and reactive oxygen species (ROS) level. ROS scavenger treatment rescues endocrine resistance in P4HA1-inactivated cells. These results indicate that P4HA1 is a key player that coordinates the crosstalk between endocrine resistance and cellular stress. These findings reveal P4HA1 as a novel therapeutic target and holds promising potential of developing new therapeutic strategies for luminal breast cancer patients with endocrine resistance. Citation Format: D. Hironaka, B. Kang, R. Xu, G. Xiong. Collagen prolyl 4-hydroxylase promotes breast cancer endocrine resistance via regulation cellular stress [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-24.