Characterization and Prognostic Impact of Fascin Expression in the Tumor Microenvironment of Triple-Negative Breast Cancer: Clues for a Tailored Therapy

Abstract

Triple-negative breast cancer (TNBC) represents 10% to 15% of all cases with breast cancer, predominantly affecting younger women. Due to the absence of hormone receptors and human epidermal growth factor receptor 2 expression, TNBC lacks effective targeted therapies, resulting in poor prognosis, with 5-year survival rates ranging from 91% for localized disease to 12% for metastatic disease. Fascin, encoded by the FSCN1 gene, is overexpressed in 88% of cases with TNBC and promotes tumor invasion, metastasis, and chemotherapy resistance. This study explored fascin as a prognostic marker and therapeutic target by analyzing its expression in the largest TNBC cohort to date and by assessing the effects of imipramine, an antidepressant that acts as a fascin inhibitor, on TNBC and luminal breast cancer cell lines. In a retrospective cohort of 145 patients with TNBC, fascin expression in tumor cells and stromal myofibroblasts correlated with high histological grade, Ki67 >30%, and BCL-2 overexpression in myofibroblasts, as well as with higher chemotherapeutic response rates in the surgical setting. Fascin expression in stromal myofibroblasts has been identified as an independent predictive marker of chemotherapeutic response and as a prognostic factor for improved survival in patients undergoing neoadjuvant chemotherapy. In vitro, imipramine significantly reduced FSCN1 expression and impaired cell migration in TNBC (MDA-MB-231) and luminal (MCF7) cell lines, with stronger effects on TNBC. These findings highlight the dual role of fascin in tumor cells and the tumor microenvironment and reinforce its potential as a biomarker for personalized TNBC therapies. Ongoing clinical trials, including histological and clinical effects of imipramine in the treatment of patients with cancer overexpressing fascin1 (HITCLIF), are exploring the efficacy of imipramine in patients with fascin-overexpressing cancers, paving the way for targeted treatment strategies.