Role of TP53 and PTEN tumor suppressor genes alterations in breast cancer response to therapy

Abstract

Background: Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. Multiple interconnected factors determine BC response to therapy and clinical outcome. TP53 and PTEN are the most frequently altered tumor suppressor genes (TSGs) in human cancers. Material and methods: To determine the potential influence of TSGs on the response to therapy we analyzed alterations of TP53 and PTEN in 90 BC specimens. The specimens were stratified based on systemic adjuvant therapy (hormonal therapy only (HT), HT and chemotherapy (HT/CHT), HT/CHT and biological therapy (HT/CHT/H). Functional inactivation of TP53 by mutations and/or loss of heterozygosity (LOH) and PTEN by LOH and/or promoter hypermethylation, were tested using single-strand conformational polymorphism (SSCP) analysis, gene sequencing, fragment analysis and methylation-specific PCR (MS-PCR) methods respectively. Results: Altered TP53 was found in 63/90 specimens (70%) while 54/90 (60%) had inactivated PTEN. Inactivation of PTEN was more frequent in tumors with altered TP53. Patients with altered TP53, lived shorter (p=0.0007) compared to those with wild type (wt) gene. The survival of patients with both TSGs altered was shorter compared to wt genes (p=0.024). Patients with wtTP53 treated with HT had longer survival (p=0.000001) when compared to all other groups. Women with both TSGs altered who received tamoxifen lived shorter than those on HT with both/one TSGs intact (p = 0.03). Conclusion: Patients with wtTP53 showed significantly better therapy response regardless of type of therapy, compared to carriers of altered TP53.