Therapy resistance remains a major barrier to improving outcomes in HER2-positive breast cancer, with dormant tumor cells (DTCs) and cancer stem cells (CSCs) playing critical roles in recurrence and treatment failure. Herein, we investigated the interplay between dormancy and CSCs features in HER2-amplified breast cancer cell models and evaluated the role of the JAK1–STAT3 axis in sustaining these therapy-resistant phenotypes. Using an in vitro dormancy model induced by HER2 inhibition, we observed a reversible quiescent state characterized by decreased proliferation and viability, accompanied by a significant increase in the CSC marker CD44. CD44 expression was rapidly induced following HER2 inhibition, preceding measurable effects on cell viability, and persisted throughout the dormancy phase. CD44-positive populations showed reduced sensitivity to HER2 inhibition and displayed robust proliferative recovery upon therapy withdrawal. Functional studies revealed that the inhibition of JAK1, but not STAT3, impaired the recovery of CD44-positive populations and decreased their proliferative capacity, suggesting a critical role for JAK1 in maintaining the CSC phenotype during therapy. These findings underscore the importance of CD44 as a marker and mediator of therapy resistance and suggest that targeting CD44-positive cells or the JAK1 signaling axis could improve the efficacy of HER2-targeted therapies. Our study provides novel insights into the mechanisms underlying dormancy and CSC induction in HER2-positive breast cancer and highlights potential strategies to mitigate therapy resistance and prevent disease recurrence.

Breast cancer is associated with systemic inflammation and increased cardiovascular risk, and anthracycline chemotherapy may contribute to persistent myocardial injury. This study aimed to evaluate acute changes in inflammatory cytokines and plasma redox status after the first anthracycline cycle and to assess long-term ventricular function after 10 years in women with breast cancer. We conducted a prospective study of 17 patients with breast cancer treated with anthracycline-based chemotherapy at Salvador Hospital, Santiago, Chile. Plasma cytokines were measured at baseline (day −7) and on day +3 after the first cycle using a MILLIPLEX Luminex^® assay. Echocardiographic assessment of left ventricular systolic and diastolic function, together with oxidative stress parameters, was performed at baseline and after 10 years of follow-up. Anthracycline exposure was associated with an acute increase in several cytokines related to inflammatory and vascular remodeling, including EGF, eotaxin, MCP-1, and VEGF. In addition, markers of redox imbalance suggested an acute pro-oxidant response after treatment. At long-term follow-up (10 years), left ventricular ejection fraction (LVEF) remained within the normal range in all patients. However, integrative echocardiographic assessment revealed impaired left ventricular relaxation, evidenced by significant reductions in the mitral inflow E/A ratio, and septal and lateral e′ velocities with respect to baseline, despite preserved estimated filling pressures. These alterations were accompanied by persistent oxidative stress, reflected by persistently elevated levels of lipid peroxidation markers, such as in vivo 8-isoprostanes. In this pilot cohort, anthracycline chemotherapy induced an early inflammatory and oxidative response that was not associated with overt long-term systolic dysfunction but was accompanied by persistent biochemical and diastolic alterations. These findings support the concept of a long-term subclinical cardiotoxic phenotype and highlight the potential value of combining echocardiographic assessment with circulating redox and inflammatory biomarkers to improve long-term cardiovascular surveillance in breast cancer survivors.