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.
Highlights
Breast cancer is the most common cancer among women worldwide [1,2]
For the Invasive Ductal Carcinoma (IDC) samples, no significant differences were found between mRNA methylthioadenosine phosphorylase (MTAP) expression and the clinico-pathological parameters
Expression of MTAP mRNA was evaluated in formalin-fixed paraffin embedded (FFPE) breast cancer samples MTAP mRNA level was 1.62 times greater in Luminal-A than in TNBC, and this difference was statistically significant (p value< 0.0001) (Fig 2)
Summary
Breast cancer is the most common cancer among women worldwide [1,2]. One of the alterations involved in the development and progression of the disease is the loss of expression of tumor suppressor genes [3].The methylthioadenosine phosphorylase (MTAP) gene is located at 9p21 and is flanked by the tumor suppressor miR-31 and the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene [4], which are approximately 100 kb away [5,6,7,8,9]. MTAP acts in the polyamine biosynthesis pathway and is important to the salvage of both adenine and methionine [3]. MTAP is ubiquitously expressed in all normal tissues but frequently lost in tumors mainly due to a co-deletion with CDKN2A. MTAP cleaves the 5’-deoxy-5’-methylthioadenosine (MTA) substrate generated during the biosynthesis of polyamines, generating adenine and 5-methylthioribose-1-phosphate (MTR-1-P). A promising therapeutic approach to cancer was proposed in 2009 by Lubin and Lubin [13], based on the addition of MTA to the treatment of MTAP-negative tumors with toxic purine analogs, like 5-fluorouracil (5-FU). Normal cells are protected from the toxic effects of purine analogs by the AMP produced from MTA. MTAP-negative tumor cells are not able to produce AMP from the added MTA, so the purine analogs are metabolized and exert their toxic effects [14]
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