Abstract 1476: OSBPL3 facilitates endoplasmic reticulum stress and stemness in triple negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is a type of aggressive breast cancer with a poor survival. Endoplasmic reticulum (ER) stress, induced by exposed to intrinsic (e.g. oncogenes) and external factors (e.g. chemotherapies), is an important factor in both tumor progression and responses to chemotherapies. Recent studies have demonstrated that the progression of ER stress may result in the emergence of cancer stem cells (CSC), which also arise as a consequence of metastasis. However, the mechanism of targeting ER stress signaling in cancer stem cells remains to be investigated. Aim: (i) To investigate the mechanistic role of Oxysterol binding protein-like 3 (OSBPL3) in TNBC and its links with breast cancer mortality, particularly caused by chemotherapeutic resistance and metastasis; and (ii) to test a hypothesis that OSBPL3 facilitates the abnormal activation of ER stress and cancer stemness, result in the resistance to chemotherapy and metastasis in TNBC. Methods: The expression level of OSBPL3 in TNBC was determined by immunohistochemical staining and the mRNA expression profiles from the TCGA database. Roles of OSBPL3 in cancer cell growth, metastasis, stemness and activation of ER stress were determined by molecular and cell biology methods. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation (ChIP), promoter luciferase reporter assay was included for detecting the transcription of OSBPL3 in TNBC. TNBC xenograft nude mice were used to study the inhibition of tumor development. Results: OSBPL3 is a novel TNBC target, which is overexpressed in TNBC tissues and significantly associated with clinical pathology of advanced TNM stage and poor prognosis of tumor patients. Mechanistically, Increased OSBPL3 induced ER stress and ER stress agonist (tunicamycin) treatment results in the translocation of XBP1, an ER stress sensor, into the nucleus to induce OSBPL3 expression through direct binding to the OSBPL3 promoter. In addition, OSBPL3 facilitates the stemness induced by ER stress via phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of stemness-related transcriptional factors, ultimately resulting in tumor metastasis and resistance to chemotherapy. Furthermore, OSBPL3-specific siRNAs encapsulated by jetPEI nanocarriers prominently inhibit tumor growth and epirubicin-induced resistance in vivo. Conclusion: We identified an important role of OSBPL3-ER stress-XBP1 feedback loop in the stemness and resistance to chemotherapy, representing a future biomarker and therapeutic target of TNBC. Citation Format: Shengyu Pu, Huimin Zhang, Yu Ren, Jianjun He, Na Hao. OSBPL3 facilitates endoplasmic reticulum stress and stemness in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1476.