Expression of Tetraspanin 4 Relative to Therapy-induced Senescence Markers in Breast Cancer in Response to Neoadjuvant Chemotherapy

Abstract

Therapy-induced senescence (TIS) is a component of breast cancer (BC) treatment. Tetraspanins have emerging roles in cancer biology. Tetraspanin 4 (TSPAN4 [NAG2]) has been implicated in tumor progression, however, its association with TIS remains unexplored. We investigated TSPAN4 expression in BC samples from patients who received neoadjuvant chemotherapy (NAC) and its association with TIS markers. Thirty-eight paired pre- and post-NAC BC samples were analyzed using immunohistochemistry (IHC) staining for TSPAN4 and TIS-associated biomarkers (Lamin B1 and Ki67). Pairwise analysis of senescence-related gene expression (LMNB1, MKI67, CDKN1A, ATM, IGFBP7, MMP2, CXCL14, and CCL5) was performed in an independent geneset of 68 paired pre- and post-NAC BC patient samples. NAC reduced the expression of senescence-associated proliferation markers Ki67 and Lamin B1 in BC samples, with 84% and 76% of patients showing decreased expression, respectively (p<0.001). Senescence-associated gene expression analysis revealed consistent upregulation of CDKN1A, ATM, IGFBP7, MMP2, CXCL14, and CCL5 post-NAC (p<0.001), while LMNB1 and MKI67 were significantly downregulated (p<0.0001 and p=0.007, respectively). A subset (15/38; 39%) of samples demonstrated upregulation of the TSPAN4 expression post-NAC (p<0.01). NAG2 was upregulated in 54/68 patients post-NAC (p<0.00001) and its expression correlated positively with senescence-associated genes. An association between TSPAN4 and TIS post-NAC was identified.