TRPM4 is overexpressed in breast cancer associated with estrogen response and epithelial-mesenchymal transition gene sets

Abstract

Ion channels form an important class of drug targets in malignancies. Transient receptor potential cation channel subfamily M member 4 (TRPM4) plays oncological roles in various solid tumors. Herein, we examined TRPM4 protein expression profile by immunohistochemistry (IHC) in breast cancer cases compared with normal breast ducts, its association with clinico-demographical parameters, and its potential function in breast cancers by Gene Set Enrichment Analysis (GSEA). Data-mining demonstrated that TRPM4 transcript levels were significantly higher in The Cancer Genome Atlas series of breast cancer cases (n = 1,085) compared with normal breast tissues (n = 112) (p = 1.03 x 10 −11 ). Our IHC findings in tissue microarrays showed that TRPM4 protein was overexpressed in breast cancers (n = 83/99 TRPM4 + ; 83.8%) compared with normal breast ducts (n = 5/10 TRPM4 + ; 50%) (p = 0.022). Higher TRPM4 expression (median frequency cut-off) was significantly associated with higher lymph node status (N1-N2 vs N0; p = 0.024) and higher stage (IIb-IIIb vs I-IIa; p = 0.005). GSEA evaluation in three independent gene expression profiling (GEP) datasets of breast cancer cases (GSE54002, n = 417; GSE20685, n = 327; GSE23720, n = 197) demonstrated significant association of TRPM4 transcript expression with estrogen response and epithelial-mesenchymal transition (EMT) gene sets (p<0.01 and false discovery rate<0.05). These gene sets were not enriched in GEP datasets of normal breast epithelium cases (GSE10797, n = 5; GSE9574, n = 15; GSE20437, n = 18). In conclusion, TRPM4 protein expression is upregulated in breast cancers associated with worse clinico-demographical parameters, and TRPM4 potentially regulates estrogen receptor signaling and EMT progression in breast cancer.

TRPM4 in Cancer—A New Potential Drug Target

“…TRPM4 expression levels have been investigated in a number of different cancers ( Figure 2 ) [ 32 , 33 , 34 , 38 , 39 , 40 , 41 , 101 , 102 , 103 , 104 , 105 , 106 ]. In most studies, TRPM4 protein expression levels were reported to be increased in tumor samples compared to healthy tissue.…”

“…In two recent studies, TRPM4 was reported to be upregulated in breast cancer samples at both the mRNA and protein levels [ 39 , 40 ]. TRPM4 mRNA was significantly upregulated in breast cancer tissue compared to normal breast tissue [ 39 ].…”

“…The breast cancer tissue displayed TRPM4-specific staining in the cytoplasm and membrane of breast cells, whereas the surrounding stromal cells were negative for TRPM4. Furthermore, increased TRPM4 staining intensity was significantly correlated with a worse prognosis, as demonstrated by a higher lymph node status and a higher pathologic prognostic stage [ 40 ].…”

“…In addition, KCTD5 regulates migration by altering Ca 2+ signaling, possibly via TRPM4 or other ion channels and Rac1 activity [ 122 , 123 ]. Moreover, in a gene set enrichment analysis of three breast cancer gene expression profiling data sets, TRPM4 expression was shown to be associated with EMT gene sets and estrogen response gene sets [ 40 ].…”

“…However, another study using TRPM4 knockout mice reported no differences in glucose-induced insulin release compared to wild-type mice [ 14 ]. Lately, growing interest has been directed toward TRPM4 and its role in several types of cancer [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. TRPM4 contributes to several cancer hallmark functions, such as cell migration, proliferation, and the epithelial to mesenchymal transition (EMT).…”