Abstract P5-06-27: OXTR inhibits breast cancer cell invasion and metastasis by regulating the post-translational modification of the COL1A1 protein to accelerate its degradation through the lysosomal pathway

Abstract Background: The oxytocin receptor (OXTR) is a hormone receptor that is highly expressed in the breast, and its expression is significantly reduced when breast tissue becomes cancerous. In addition to serving as a receptor for receiving stimulation from hormones, neurotransmitters, and growth factors to mediate their effects, the biological function and molecular mechanism of OXTR itself in breast cancer (BrCa) are still unclear. Methods: Using quantitative PCR (qRT-PCR), Western blot, immunohistochemistry (IHC), and public database analysis, the expression of OXTR in BrCa adjacent normal tissues, BrCa tissues, and metastatic tissues, as well as its correlation with prognosis were evaluated. The migration and invasion functions of OXTR were analyzed by wound-healing and transwell assays in vitro. Lung metastatic tumor models were used to study the invasion and metastasis of OXTR in vivo. RNA-seq, Western blot, immunofluorescence (IF), immunoprecipitation (IP) and Co-IP were further applied to determine the detailed mechanism. Results: OXTR is downregulated in BrCa tissues, especially in distant metastases. Patients with lower OXTR expression have worse overall survival (OS) and distant metastasis-free survival (DMFS). In functional experiments, overexpression of OXTR suppresses BrCa cell migration, invasion and metastasis in vitro and in vivo. Conversely, knockdown of OXTR increased BrCa cell spreading. OXTR functions by inhibiting the expression of the oncoprotein collagen type I alpha 1 chain (COL1A1), which is closely associated with epithelial-mesenchymal transition (EMT). The mechanism is mainly that OXTR causes the decrease of COL1A1 protein phosphorylation and the increase of O-GlcNAcylation by down-regulating CDK1. However, O-GlcNAcylated COL1A1 is unstable and can be easily degraded by the lysosomal pathway. Conclusions: This study extends the ligand-independent function of OXTR in BrCa and highlights the role of OXTR in suppressing invasion and metastasis of BrCa cells, as well as predicting prognosis. This study elucidates the specific mechanism by which OXTR accelerates the degradation of COL1A1 protein by regulating its post-translational modifications (PTMs), thereby affecting the malignant progression of cancer cell metastasis. These findings suggest that OXTR may serve as a marker to predict the metastatic potential or prognosis of BrCa. Citation Format: Qing Shao. OXTR inhibits breast cancer cell invasion and metastasis by regulating the post-translational modification of the COL1A1 protein to accelerate its degradation through the lysosomal pathway [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-06-27.