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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.

SUBMITTER: Wong KK

PROVIDER: S-EPMC7266295 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wong Kah Keng KK Hussain Faezahtul Arbaeyah FA

PloS one 20200602 6

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 th ...[more]

PMID: 32484822

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Project description:We propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII) with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes ≥ 3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of specific mediators may offer a useful supplementary strategy to circumvent the effects of loss of endocrine sensitivity.

Project description:BackgroundCingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and mechanistic analyses and proposes a potential targeted therapeutic approach.MethodsIn a high-cancer-density family without known pathogenic variants, we performed tumor-targeted and germline whole-genome sequencing to identify novel cancer-associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c.3560C > T was identified as a potential cancer-risk allele. Both wild-type (WT) (c.3560C > C) and variant (c.3560C > T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluorescence analysis, migration and invasion assays, two-dimensional gel electrophoresis with mass spectrometry, immunoprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c.3560C > T.ResultsIn cancer cell lines and orthotopic animal models, CGN c.3560C > T enhanced tumor progression with reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithelial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial-mesenchymal transition (EMT). Proteomic analysis was conducted to investigate the elements driving EMT in CGN c.3560C > T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1. IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harboring CGN c.3560C > T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treatment with NSC23766, a selective inhibitor for Rac1-GEF interaction, resulted in the inactivation of Rac1. This intervention mitigated the EMT program in cancer cells carrying CGN c.3560C > T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c.3560C > T.ConclusionsCGN c.3560C > T leads to IQGAP1 overexpression, subsequently triggering Rac1-dependent EMT. Targeting activated Rac1 is a strategy to impede the advancement of cancers carrying this specific variant.

Project description:BackgroundEstrogen is involved in the pathophysiological process of benign prostatic hyperplasia (BPH), in which epithelial-mesenchymal transition (EMT) plays an important role. Upregulation of aquaporin (AQP) 5, which is directly activated by estrogen, has been reported to promote EMT in multiple cells. This study aimed to examine the effects of AQP5 on estrogen-induced EMT in the prostate.MethodsNormal prostate (NP) tissue samples without any histopathological changes and BPH tissue samples with pathologically confirmed hyperplasia were obtained. An EMT cell model was subsequently established by adding estradiol (E2) to RWPE-1 cells, after which AQP5 knockdown was performed. Tissue morphological and immunohistochemical features were examined using hematoxylin-eosin and immunohistochemical staining. Western blot analysis was performed to determine the expression of AQPs, estrogen receptors, and EMT-related proteins. Cell proliferation was assessed and supernatants were collected for enzyme-linked immunosorbent assay to determine transforming growth factor-β1 (TGF-β1) concentrations. Immunofluorescence staining was performed to assess protein expressions in RWPE-1 cells.ResultsBPH tissues exhibited greater EMT (TGF-β1: 1.362 ± 0.196 vs. 0.107 ± 0.067, P = 0.003; vimentin: 1.581 ± 0.508 vs. 0.221 ± 0.047, P < 0.001; E-cadherin: 0.197 ± 0.188 vs. 1.344 ± 0.088, P < 0.001), higher AQP5 (1.268 ± 0.136 vs. 0.227 ± 0.055, P < 0.001) and estrogen receptor (ER) α (1.250 ± 0.117 vs. 0.329 ± 0.134, P < 0.001) expression but lower ERβ (0.271 ± 0.184 vs. 1.564 ± 0.130, P < 0.001) expression than NP tissues. E2-stimulated cells had higher AQP5 expression (1.298 ± 0.058 vs. 1.085 ± 0.104, P = 0.049), increased cell proliferation (1.510 ± 0.089 vs.1.000 ± 0.038, P < 0.001), and EMT (TGF-β1 concentration: 0.352 ± 0.021 ng/mL vs. 0.125 ± 0.014 ng/mL, P < 0.001; vimentin: 1.641 ± 0.120 vs. 0.188 ± 0.020, P = 0.002; E-cadherin: 0.075 ± 0.030 vs. 0.843 ± 0.046, P < 0.001) than controls. E2-stimulated cells with AQP5 knockdown exhibited decreased EMT (TGF-β1 concentration: 0.223 ± 0.041 ng/mL vs. 0.352 ± 0.021 ng/mL, P = 0.016; vimentin: 0.675 ± 0.056 vs. 1.641 ± 0.120, P = 0.001; E-cadherin: 0.159 ± 0.037 vs. 0.075 ± 0.030, P = 0.040) than E2-stimulated cells with non-related small interfering RNA (siRNA).ConclusionOur findings suggest that estrogen induces BPH possibly by promoting AQP5 expression. Hence, AQP5 might be a novel target for modulating EMT in prostate epithelial cells.

Dataset Information

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

Publications

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

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