Abstract 3456: Differential impact of oncostatin M (OSM) on EMT and biomechanical properties of HER2+ and HER2- breast cancer

Abstract In the United States, breast cancer (BC) is projected to cause over 43,000 deaths in 2025, despite significant advances in diagnostic and therapeutic strategies. Mortality is primarily attributed to late-stage diagnosis with distant metastasis. One key mechanism that enhances the metastatic potential of breast carcinoma cells is the epithelial-to-mesenchymal transition (EMT), a process in which cells lose their apical-basal polarity and acquire a mesenchymal-like phenotype; thereby increasing their motility and invasiveness. The treatment choice for each BC patient is very complex since it depends on the presence or absence of hormonal receptors and epidermal growth factor receptor 2 (HER2) expressed by the tumor cells. This research distinguishes between patients whose cancer cells overexpress HER2 (HER2-positive; HER2+) and those who do not (HER2-negative; HER2-), representing around 30% and 70% of all BC diagnoses, respectively. Oncostatin M (OSM) is an interleukin 6 (IL-6)-family proinflammatory cytokine produced in the BC tumor microenvironment in a paracrine manner by macrophages and neutrophils, as well as in an autocrine fashion by the tumor cells. Clinical data indicates a negative correlation between elevated OSM tumor levels and patient survival. OSM plays a critical role in metastasis through multiple mechanisms, including promoting the secretion of pro-metastatic molecules such as VEGF, LOXL2, and IL-6, increasing circulating tumor cell (CTC) numbers, and facilitating metastasis to distant organs such as bone and lung as observed in vivo. Our laboratory has demonstrated that OSM induces EMT in HER2- BC cell lines, but little is known about its role in HER2+ BC. Thus, we aimed to investigate the differential effects of OSM on metastatic potential, focusing on EMT and cell motility in HER2+ versus HER2- BC models. Using qRT-PCR, western blot analysis, and immunofluorescent staining on HER2+ and HER2- BC cell lines, we show that OSM treatment downregulates tight junction proteins, essential for maintaining epithelial apical-basal polarity. Additionally, we detected upregulation of key EMT transcription factors, including SNAIL, and a marked rearrangement of actin filaments, which collectively promote a mesenchymal-like phenotype in these cells. By employing nanoindentation assays with atomic force microscopy (AFM) to measure biomechanical properties, we establish for the first time, a link between OSM and increased membrane elasticity, a hallmark of motile cells in breast cancer. This research aims to understand the unique role OSM plays in HER2+ and HER2- breast cancer in promoting metastasis and will provide a mechanistic understanding of how this occurs and offer a molecular framework for identifying patients who may benefit from anti-OSM therapies that are in development. Citation Format: Maria Pou, Kali Woods, Laura Bond, Cheryl Jorcyk. Differential impact of oncostatin M (OSM) on EMT and biomechanical properties of HER2+ and HER2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3456.