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.
Highlights
Ion channels form an important class of therapeutic target where they account for nearly onefifth of all human druggable proteins [1]
Our initial data-mining showed that TRPM4 transcript was frequently expressed in breast cancer cell lines according to the Cancer Cell Line Encyclopedia (CCLE) database [43]
In The Cancer Genome Atlas (TCGA) breast cancer cases as curated by Gene Expression Profiling Interactive Analysis 2 database [44], TRPM4 transcript levels were significantly higher in breast cancer cases (n = 1,085) compared with normal breast tissues (n = 112) (p = 1.03 x 10−11) (Fig 1B)
Summary
Ion channels form an important class of therapeutic target where they account for nearly onefifth of all human druggable proteins [1]. Ion channels contribute to various malignant phenotypes of cancer cells through regulating the transport of the universal signaling ion calcium. TRPM4 overexpression in breast cancer (Ca2+) [2]. On the basis of sequence homology, mammalian TRP channels can be categorized into six subfamilies including the TRPM group of ion channels [4]. The TRPM subfamily consists of eight ion channel members (TRPM1-8) where each contains six transmembrane domains and a loop that forms the channel’s pore [5, 6]
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