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Characterization of MTAP Gene Expression in Breast Cancer Patients and Cell Lines
Sarah Franco Vieira de Oliveira1, Monica Ganzinelli2, Rosaria Chilà2
1Department of Genetics, Federal University of Paraná, Curitiba, Paraná, Brazil.
Abstract:
MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors´ MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC.
Insights
Methylthioadenosine phosphorylase (MTAP) acts as a tumor suppressor in breast cancer. Lower MTAP expression in triple-negative breast tumors suggests potential therapeutic strategies targeting MTAP status.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The methylthioadenosine phosphorylase (MTAP) gene is crucial for adenine and methionine salvage pathways.
- MTAP is located at 9p21, a region frequently deleted in breast cancer, similar to the tumor suppressor gene CDKN2A.
- Previous studies suggest MTAP functions as a tumor suppressor, with potential therapeutic implications based on tumor MTAP status.
Purpose of the Study:
- To investigate the role of MTAP and CDKN2A in breast cancer by analyzing their gene and protein expression and promoter methylation.
- To evaluate the therapeutic potential of targeting MTAP in breast cancer cell lines.
- To assess MTAP expression in different breast tumor subtypes and normal tissues.
Main Methods:
- Quantitative real-time PCR (RT-qPCR) for gene expression analysis.
- Western blotting for protein expression analysis.
- Cytotoxicity assays with de novo adenine synthesis inhibitors (5-FU, AZA, MTX) following MTAP gene knockdown.
- Analysis of MTAP expression in fresh tumor/normal tissue pairs and formalin-fixed paraffin-embedded (FFPE) samples from Luminal-A and triple-negative breast tumors (TNBC).
Main Results:
- MTAP gene knockdown increased breast cancer cell line sensitivity to de novo adenine synthesis inhibitors, particularly 5-FU.
- No statistically significant difference in MTAP expression was observed between fresh breast tumors and paired normal tissues.
- MTAP expression was significantly higher in Luminal-A breast tumors compared to TNBC.
Conclusions:
- MTAP functions as a tumor suppressor in breast cancer, with its expression potentially correlating with tumor subtype.
- The reduced expression of MTAP in aggressive TNBC suggests its potential as a therapeutic target for this subtype.
- Targeting de novo adenine synthesis pathways, especially with 5-FU, may be a viable strategy for MTAP-deficient breast cancers.
