Role of P4HA1 in Endocrine Resistance of Breast Cancer

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Abstract: Tamoxifen is the oldest and the most widely used selective estrogen receptor modulators. Fulvestrant is a selective estrogen receptor down-regulator which blocks and damages estrogen receptors. Fulvestrant is introduced to clinical as second-line therapy post disease progression after tamoxifen. Endocrine treatment is the first-line therapy for estrogen receptor positive breast cancer patients. However, 30%-50% of the breast cancer patients with five to ten years of treatment acquire resistance to endocrine therapy. Resistance to endocrine therapy and recurrence is the leading cause of mortality in breast cancer patients. Prolyl hydroxylation (P4H), is an enzyme hydroxylates proline into 4-hydroxyproline of collagens and other proteins with the -X-Pro- Gly- sequences as collagens in the endoplasmic reticulum. P4HA1, the alpha subunit of P4H1, is responsible for both peptide binding and catalytic activity. In this study, we found that increased expression of P4HA1 was detected in endocrine therapy resistant luminal breast cancer cells compared with endocrine therapy sensitive cells. High P4HA1 expression significantly correlates with short relapse-free survival in luminal breast cancer patients. Inactivation of P4HA1 protein sensitized endocrine resistance luminal cancer cells to 4- Hydroxytamoxifen (4OHT) or fulvestrant treatment, accompanied by increased reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. These preliminary data indicate that P4HA1 is an important regulator for endocrine resistance of breast cancer. We hypothesize that inhibition of P4HA1 sensitizes luminal breast cancer cells to endocrine therapy by inducing ROS-ER stress pathway. To investigate the importance of P4HA1 for endocrine resistance, we will introduce P4HA1 protein expression in endocrine sensitive luminal breast cancer cell lines. We will examine resistance to 4OHT or fulvestrant treatment, ER stress level, as well as ROS levels in P4HA1-overexpression cells under 4OHT or fulvestrant treatment. We will perform rescue experiments in P4HA-silenced endocrine resistant cells using ROS inhibitor. For the in vivo study, we will use endocrine resistant luminal breast cancer cell lines orthotropic xenograft model, and resistance luminal breast cancer patient- derived-xenograft (PDX) models. We will determine whether inactivation of P4HA1 renders these endocrine resistant tumors sensitive to tamoxifen or fulvestrant treatment in vivo, and examine whether the overwhelmed ER stress and ROS levels are associated with endocrine sensitivity in tumors. In summary, this investigation will uncover a novel uncanonical role of P4HA1 in endocrine resistance by regulation ROS-ER stress pathway, and explore P4HA1 as a novel therapeutic target for combinatorial therapy for endocrine resistant luminal breast cancer patients.