ROR1 Epigenetic Grip on CREB3L1, a Tumor Suppressor in Triple-Negative Breast Cancer

Abstract ID 128510 Poster Board 055 Over 300,000 new cases of invasive breast cancer are projected in the United States alone for 2024. Triple-Negative breast cancer (TNBC) is the most aggressive form of breast cancer. It is also the most difficult to treat due to the lack of all three common receptors used to target the cancer (ER+, PR+, HER2). Therefore, patients are often treated with abrasive chemotherapy drugs that can both result in undesirable side effects and create a resistance to treatment. TNBC tumors are highly heterogeneous and contain many different types of CSCs, leading to increased epithelial to mesenchymal transition (EMT). Thus, CSCs contribute to the high instance of chemotherapy resistance in TNBC patients. The focus of our lab is to uncover potential biomarkers that could be utilized to specifically target TNBC cells in patients. In particular, we study an oncogene known as receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is only highly expressed in cancerous tissue and during fetal development. TNBC patients with high ROR1 expression have been found to have poor prognosis and decreased overall survival rate. ROR1 increases TNBC metastasis and drug resistance via signaling pathways such as PI3K/AKT. Through single cell RNA sequencing, our lab discovered that TNBC cell lines with high ROR1 expression also had decreased cAMP responsive element binding protein 3 like 1 (CREB3L1) expression. cAMP responsive element binding protein 3 like 1 (CREB3L1) is a component of the unfolded protein response (UPR) and has been found to function as a tumor suppressor. In TNBC, CREB3L1 expression is diminished due to its promoters being bombarded with methyl groups by DNA methyltransferases (DNMTs), such as DNMT3A. MicroRNAs (miRNAs) work to activate the expression of DNMTs. In breast cancer, increased expression of mirna29b resulted in decreased overall survival in patients compared to those with low mirna29b expression. We hypothesize that ROR1 epigenetically regulates CREB3L1 by increasing the activity of DNMT3A via increased miR29b expression in TNBC. Preliminary results show that the knockdown of ROR1 expression causes an increase of CREB3L1 expression while decreasing DNMT3A expression in TNBC cell lines. We also see a decrease in miR29b expression following ROR1 knockdown, via qPCR analysis. This study will help to identify a novel oncogenic signaling pathway in TNBC that can be targeted for patient therapy.