Abstract
Cell transmembrane receptors and extracellular matrix components play a pivotal role in regulating cell activity and providing for the concerted integration of cells in the tissue structures. We have assessed DNA methylation in the promoter regions of eight integrin genes, two nidogen genes, and the dystroglycan gene in normal breast tissues and breast carcinomas (BC). The protein products of these genes interact with the basement membrane proteins LAMA1, LAMA2, and LAMB1; abnormal hypermethylation of the LAMA1, LAMA2, and LAMB1 promoters in BC has been described in our previous publications. In the present study, the frequencies of abnormal promoter hypermethylation in BC were 13% for ITGA1, 31% for ITGA4, 4% for ITGA7, 39% for ITGA9, 38% for NID1, and 41% for NID2. ITGA2, ITGA3, ITGA6, ITGB1, and DAG1 promoters were nonmethylated in normal and BC samples. ITGA4, ITGA9, and NID1 promoter hypermethylation was associated with the HER2 positive tumors, and promoter hypermethylation of ITGA1, ITGA9, NID1 and NID2 was associated with a genome-wide CpG island hypermethylated BC subtype. Given that ITGA4 is not expressed in normal breast, one might suggest that its abnormal promoter hypermethylation in cancer is non-functional and is thus merely a passenger epimutation. Yet, this assumption is not supported by our finding that it is not associated with a hypermethylated BC subtype. ITGA4 acquires expression in a subset of breast carcinomas, and methylation of its promoter may be preventive against expression in some tumors. Strong association of abnormal ITGA4 hypermethylation with the HER2 positive tumors (p = 0.0025) suggests that simultaneous presence of both HER2 and integrin α4 receptors is not beneficial for tumor cells. This may imply HER2 and integrin α4 signaling pathways interactions that are yet to be discovered.
Highlights
Cell transmembrane receptors and extracellular matrix components play a pivotal role in regulating cell functioning and ensure concerted cell integration in the tissue structure
Based on the results of MSRE-PCR, the genes were classified into two categories: genes with CpG islands nonmethylated in normal breast tissues but prone to abnormal hypermethylation in breast carcinomas (BC) (ITGA1, ITGA4, ITGA7, ITGA9, NID1, and NID2), and genes with CpG islands found to be nonmethylated in all breast tissues, no matter normal or cancerous (ITGA2, ITGA3, ITGA6, ITGB1, and DAG1)
Our MSRE-PCR results demonstrated in Table 1 recapitulate the ENCODE representation bisulfite sequencing (RRBS) data for the ITGA1, ITGA4, ITGA9, NID1 and NID2 promoters approving the validity of our approach
Summary
Cell transmembrane receptors and extracellular matrix components play a pivotal role in regulating cell functioning and ensure concerted cell integration in the tissue structure. Malignant transformation is associated with dramatic alterations in cell signaling. Such alterations affect both cancer cell behavior and components of the tumor microenvironment. A total of 18 α and 8 β subunits are known today Their pairwise interactions produce at least 24 αβ receptor combinations. As their important functions, integrins mediate bidirectional signaling and contribute to cell adhesion by forming hemidesmosomes and focal contacts. Given that multiple functions are mediated by integrins, one can assume that integrins are involved in cell malignant transformation, invasion, and metastasis. Ample data have accumulated to date to characterize the role that integrins play in morphogenesis and function of the breast epithelium, and changes in integrin expression have been observed in B C4
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