Expression and Subcellular Localization of TP73 Isoforms as Prognostic Factors in Breast Cancer Molecular Subtypes

GOMEZ LAURA C; SOTTILE MAYRA L; REDONDO ANALIA L; VARGAS ROIG LAURA M

Buenos Aires

Simposio; BUENOS AIRES BREAST CANCER SYMPOSIUM - 2024; 2024

Breast cancer (BC) is a prevalent disease in our country. BC are classified into molecular subtypes based on geneexpression variations: normal breast-like, luminal A, luminal B, HER2, and basal-like. We previously reported significantdifferences in TP73 methylation among these subtypes. Luminal A tumors often show unmethylated TP73, while allbasal-like tumors exhibit methylated TP73. The p73 protein is structurally and functionally like the p53 tumor protein.However, the TP73 gene produces multiple isoforms that have antagonistic properties.Here, we analyzed the expression differences of TP73 exons in the TCGA breast cancer RNASeq dataset using EdgeRtools. This allowed us to identify the prevalent isoforms expressed in each BC subtype. Additionally, we examined theexpression and subcellular localization of the TA-p73 and ΔNp73 isoforms in 137 invasive breast tumors and 5 BC celllines using immunohistochemistry and immunofluorescence techniques. Our results revealed that TP73 is overexpressedin all BC subtypes. Surprisingly, this up-regulation depends mostly on the over-expression of exons corresponding to theTAp73-specific domains. Notably, significant downregulation of the 4th exon was observed in all subtypes, suggesting adifferential gene promoter usage favoring TAp73 isoform expression. Furthermore, we found that the TA-p73 isoformpredominantly localized in the nucleus of luminal BC tumors, while basal-like and ErbB2+ tumors exhibited cytoplasmicexpression. In contrast, the ΔNp73 isoform was mainly localized in the cytoplasm of all breast tumor subtypes.Additionally, the TA-p73 isoform was mostly nuclear in luminal BC cell lines, whereas it was primarily cytoplasmic inbasal-like cell lines. These findings provide valuable insights into the expression patterns and subcellular localization ofTP73 isoforms in different BC subtypes, highlighting the complex biology of TP73 and its potential implications forprognosis and treatment.