Fascin Drives Breast Cancer Cell Proliferation Partly by Modulating the Cell Cycle Checkpoint Regulators of the G1-S Phase

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Despite therapeutic advances, disease relapse and metastasis remain major challenges and drivers of mortality. Fascin, an actin-bundling protein, promotes BC progression by enhancing drug resistance. However, the role of fascin in proliferation, a hallmark of cancer, and the underlying mechanism remain poorly elucidated. In this study, bioinformatics analysis of publicly available BC datasets, gene manipulation (gain and loss of function) in BC cell lines, flow cytometry, Western blots, and a real-time cell analyzer (RTCA) were employed to assess the role of fascin in proliferation. The clinical relevance of bioinformatics data and in vitro findings was assessed in BC patient samples using immunohistochemistry. <i>FSCN1</i> expression exhibited a significant correlation with proliferation signature scores in BC datasets. Ectopic expression of fascin in fascin-negative SK-BR-3 and its silencing in fascin-positive MDA-MB-231 BC cell lines demonstrated its direct role in driving proliferation. In-depth bioinformatics analyses revealed a significant correlation between <i>FSCN1</i> and the cell cycle signature score, particularly the G1-S signature score gene set. Indeed, fascin accelerated the cell cycle progression of synchronized cells from the G to S phase. Mechanistically, fascin upregulated nuclear SKP2 levels and reduced p27 expression-important G1-S cell cycle checkpoint regulators. Immunohistochemistry in samples from 68 patients demonstrated significant correlations between fascin and Ki-67 expression, in addition to SKP2 overexpression and p27 downregulation. Collectively, these data demonstrate the role of fascin as a driver of the G1-S-phase transition during cell cycle proliferation, thereby revealing new opportunities for targeted therapeutic intervention.