Mutation analysis and mRNA expression of trail‐receptors in human breast cancer

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Abstract
The chromosome region 8p12‐p22 shows frequent allelic loss in a variety of human malignancies, including breast cancer (BC). The tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐receptors TRAIL‐R1, ‐R2, ‐R3 and ‐R4 are located on 8p21‐p22 and might be candidate tumor suppressor genes in this region. To evaluate the involvement of TRAIL receptors in breast carcinogenesis, we have analyzed the entire coding region of TRAIL‐R2 and the death domain (DD) regions of TRAIL‐R1 and ‐R4 for the detection of somatic mutations in a series of breast tumors, lymph node metastases and BC cell lines. Overall, we detected 1, 11 and 3 alterations in the TRAIL‐R1, ‐R2 and ‐R4 genes, respectively. Although functional studies have not yet been performed, we assume that most of these alterations do not alter the function of TRAIL‐receptors. Additionally, we analyzed individuals from BC families for the detection of TRAIL‐R2 germline mutations. One alteration has been found in the Kozak consensus motif at position ‐4 with respect to the translation initiation AUG [1‐4 (C→A)]. We further studied the mRNA expression of TRAIL and the 4 TRAIL receptors. In BC cell lines, a strongly decreased mRNA expression of TRAIL, TRAIL‐R1, ‐R3 and ‐R4 was found, whereas the expression of TRAIL‐R2 was only slightly reduced. In breast tumors, a 1.2–3.6‐fold reduction of mRNA signals of the 5 genes was observed. No correlation was found between the expression level of TRAIL and the receptor mRNAs and clinicopathologic variables and between the expression of TRAIL‐R2 and TP53 mutation status and loss of heterozygosity (LOH) at 8p21‐p22. Taken together, we cannot exclude the involvement of TRAIL‐receptors in BC. Our mutation studies indicate that DD receptor mutations occur at low frequency and are not the primary cause for the altered mRNA expression of TRAIL and TRAIL‐receptors in BC.

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