MMP1-induced NF-κB activation promotes epithelial-mesenchymal transition and sacituzumab govitecan resistance in hormone receptor-positive breast cancer

Sacituzumab govitecan (SG), a novel antibody-drug conjugate (ADC), shows promise in the treatment of breast Cancer (BC); however, drug resistance limits its clinical application. Matrix metalloproteinase 1 (MMP1), which is overexpressed in many tumor types, plays a key role in tumor metastasis and drug resistance. The involvement of MMP1 in SG resistance in metastatic hormone receptor-positive (HR + ) BC has not been previously reported. In this study, we employed various in vitro and in vivo approaches to investigate the role of MMP1 in SG resistance in BC. MMP1 expression was manipulated in different BC cell lines through lentiviral transfection and small interfering RNA techniques. Key methodologies included Western blot, quantitative Reverse transcription PCR, and RNA Sequencing to assess marker expression and identify differentially expressed genes. Functional assays were conducted to evaluate cell viability, proliferation, invasion, and migration. In vivo, a cell-derived xenograft model in nude mice was utilized to assess tumor growth and drug response. Bioinformatics analyses further explored MMP1 expression and its clinical relevance across different Cancer types. Our findings indicate that MMP1 is overexpressed by approximately 30-fold in HR + BC tissues and is associated with poorer prognosis among HR + BC patients. Furthermore, our analysis reveals that HR + BC with high MMP1 expression displays resistance to SG, supporting the hypothesis that MMP1 plays a key role in regulating ADC resistance. Mechanistic studies demonstrate that MMP1 can activate the NF-κB pathway, which subsequently influences the epithelial-mesenchymal transition, thereby contributing to SG resistance. Ultimately, our research underscores the potential of MMP1 as a therapeutic target and biomarker, facilitating personalized treatment strategies that could enhance patient outcomes in BC therapy.