Elevated NIS Expression Correlates with Chemoresistance in Triple-Negative Breast Cancer: Potential Link to FOXA1 Activity

Background: Sodium/iodide symporter (NIS) is a membrane protein involved in iodide transport into cells, making it a key component of thyroid physiology and radioiodine therapy for thyroid cancer. Although NIS is expressed in many extrathyroidal tissues, including breast tumors, its functional role and prognostic significance in these contexts remain a subject of active investigation. Understanding the mechanisms regulating NIS, its influence on cellular processes such as migration and metastasis, and its connection with transcription factors like FOXA1 could contribute to the development of new therapeutic strategies for breast cancer treatment. This study aims to investigate the correlation between sodium/iodide symporter (NIS) expression and response to neoadjuvant chemotherapy in patients with triple-negative breast cancer (TNBC). Methods: The current retrospective study included 161 TNBC patients who received neoadjuvant chemotherapy followed by mastectomy. NIS expression was assessed via immunohistochemistry, graded semi-quantitatively from 0 to 3+. The Residual Cancer Burden (RCB) scale was used to evaluate the response to chemotherapy. Statistical analysis included Lilliefors tests and Kendall’s tau correlation coefficient. Publicly available Cancer Genome Atlas datasets were analyzed to assess the relationship between NIS and FOXA1 expression. Results: NIS immunopositivity was observed in 69.5% of TNBC samples compared to 63.3% GATA-3-positive and 31.0% of Mammaglobin-positive samples. While no significant correlation was found between NIS expression and age, TNM stage, or Ki-67, a statistically significant moderate positive correlation (τ = 0.481, p < 0.01) was identified between NIS expression and RCB index, indicating that higher NIS expression was associated with a poorer response to neoadjuvant chemotherapy. TCGA data analysis revealed a statistically significant increase in NIS mRNA expression in FOXA1-mutated TNBC samples compared to FOXA1-wild-type samples (p < 0.05). Younger patients exhibited higher Ki-67 levels (τ = −0.416, p < 0.05). Conclusions: Higher NIS expression correlates with chemoresistance to neoadjuvant chemotherapy in TNBC patients. This phenomenon may be linked to FOXA1 activity, suggesting that NIS may represent a potential biomarker for chemoresistance in TNBC. The inverse correlation between patient age and Ki-67 levels may be associated with a different mutational landscape in younger patients. © 2025 by the authors.