Overexpression of WT1 in all molecular subtypes of breast cancer and its impact on survival: exploring oncogenic and tumor suppressor roles of distinct WT1 isoforms

Hind Ben Haj Othmen; Houcemeddine Othman; Oussema Khamessi; Ilhem Bettaieb; Sonia Gara; Maher Kharrat

doi:10.1007/s11033-024-09450-4

Overexpression of WT1 in all molecular subtypes of breast cancer and its impact on survival: exploring oncogenic and tumor suppressor roles of distinct WT1 isoforms

Mol Biol Rep. 2024 Apr 20;51(1):544. doi: 10.1007/s11033-024-09450-4.

Authors

Hind Ben Haj Othmen¹, Houcemeddine Othman², Oussema Khamessi³, Ilhem Bettaieb⁴, Sonia Gara^{5

6}, Maher Kharrat⁵

Affiliations

¹ Human Genetics Laboratory LR99ES10, Faculty of Medicine of Tunis, University of Tunis El Manar, 1007, Tunis, Tunisia. hindbenhajothmen@gmail.com.
² Laboratory of Cytogenetics, Molecular Genetics and Biology of Human Reproduction, University Hospital Farhat Hached, Sousse, Tunisia.
³ Biotechnology Institut of Sidi Thabet, University of Manouba, Ariana BP-66, 2010, Manouba, Tunisia.
⁴ Laboratory of Immunohistocytology, Salah Azaiez Cancer Institute, 1006, Tunis, Tunisia.
⁵ Human Genetics Laboratory LR99ES10, Faculty of Medicine of Tunis, University of Tunis El Manar, 1007, Tunis, Tunisia.
⁶ Laboratory of Clinical Biochemistry, Salah Azaiez Cancer Institute, 1006, Tunis, Tunisia.

PMID: 38642153
DOI: 10.1007/s11033-024-09450-4

Abstract

Background: Breast cancer is a highly heterogeneous solid tumor, posing challenges in developing targeted therapies effective for all mammary carcinoma subtypes. WT1 emerges as a promising target for breast cancer therapy due to its potential oncogenic role in various cancer types. Previous works have yielded inconsistent results. Therefore, further studies are needed to clarify the behavior of this complex gene in breast cancer.

Methods and results: In this study, we examined WT1 expression in both Formalin Fixed Paraffin Embedded breast tumors (n = 41) and healthy adjacent tissues (n = 41) samples from newly diagnosed cases of ductal invasive breast cancer. The fold change in gene expression between the tumor and healthy tissue was determined by calculating 2^-∆∆Ct. Disease-free survival analysis was computed using the Kaplan-Meier method. To identify the expression levels of different WT1 isoforms, we explored the ISOexpresso database. Relative quantification of the WT1 gene revealed an overexpression of WT1 in most cases. The percentage of patients surviving free of disease at 8 years of follow-up was lower in the group overexpressing WT1 compared to the group with down-regulated WT1.

Conclusions: Interestingly, this overexpression was observed in all molecular subtypes of invasive breast cancer, underscoring the significance of WT1 as a potential target in all these subtypes. The observed WT1 down-expression in a few cases of invasive breast cancer, associated with better survival outcomes, may correspond to the down-regulation of a particular WT1-KTS (-) isoform: the WT1 A isoform (EX5-/KTS-). The co-expression of this WT1 oncogenic isoform with a regulated WT1- tumor suppressor isoform, such as the major WT1 F isoform (EX5-/KTS +), could also explain such survival outcomes. Due to its capacity to adopt dual roles, it becomes imperative to conduct individual molecular expression profiling of the WT1 gene. Such an approach holds great promise in the development of personalized treatment strategies for breast cancer.

Keywords: Breast cancer; Expression; Isoform; Oncogene; Tumor suppressor; WT1.

MeSH terms

Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Female
Genes, Tumor Suppressor
Humans
Protein Isoforms / genetics
Protein Isoforms / metabolism
WT1 Proteins* / genetics
WT1 Proteins* / metabolism

Substances

Protein Isoforms
WT1 protein, human
WT1 Proteins