Transcriptional responses to direct and indirect TGFB1 stimulation in cancerous and noncancerous mammary epithelial cells.
Humans
Transforming Growth Factor beta1
/ pharmacology
Epithelial Cells
/ metabolism
Breast Neoplasms
/ pathology
Epithelial-Mesenchymal Transition
/ genetics
MCF-7 Cells
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Signal Transduction
/ drug effects
Transcription, Genetic
/ drug effects
Mammary Glands, Human
/ pathology
Bystander effect
Cell cycle
Cell death
EMT
Estrogen signaling
MCF10A
MCF7
Mammary epithelial cells
TGFβ signaling
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
28 Oct 2024
28 Oct 2024
Historique:
received:
26
03
2024
accepted:
07
09
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Transforming growth factor beta (TGFβ) is important for the morphogenesis and secretory function of the mammary gland. It is one of the main activators of the epithelial-mesenchymal transition (EMT), a process important for tissue remodeling and regeneration. It also provides cells with the plasticity to form metastases during tumor progression. Noncancerous and cancer cells respond differently to TGFβ. However, knowledge of the cellular signaling cascades triggered by TGFβ in various cell types is still limited. MCF10A (noncancerous, originating from fibrotic breast tissue) and MCF7 (cancer, estrogen receptor-positive) breast epithelial cells were treated with TGFB1 directly or through conditioned media from stimulated cells. Transcriptional changes (via RNA-seq) were assessed in untreated cells and after 1-6 days of treatment. Differentially expressed genes were detected with DESeq2 and the hallmark collection was selected for gene set enrichment analysis. TGFB1 induces EMT in both the MCF10A and MCF7 cell lines but via slightly different mechanisms (signaling through SMAD3 is more active in MCF7 cells). Many EMT-related genes are expressed in MCF10A cells at baseline. Both cell lines respond to TGFB1 by decreasing the expression of genes involved in cell proliferation: through the repression of MYC (and the protein targets) in MCF10A cells and the activation of p63-dependent signaling in MCF7 cells (CDKN1A and CDKN2B, which are responsible for the inhibition of cyclin-dependent kinases, are upregulated). In addition, estrogen receptor signaling is inhibited and caspase-dependent cell death is induced only in MCF7 cells. Direct incubation with TGFB1 and treatment of cells with conditioned media similarly affected transcriptional profiles. However, TGFB1-induced protein secretion is more pronounced in MCF10A cells; therefore, the signaling is propagated through conditioned media (bystander effect) more effectively in MCF10A cells than in MCF7 cells. Estrogen receptor-positive breast cancer patients may benefit from high levels of TGFB1 expression due to the repression of estrogen receptor signaling, inhibition of proliferation, and induction of apoptosis in cancer cells. However, some TGFB1-stimulated cells may undergo EMT, which increases the risk of metastasis. Transforming growth factor beta (TGFβ) is a multifaceted cytokine that controls numerous physiological and pathological processes during development and carcinogenesis. Its best-known function is the activation of epithelial–mesenchymal transition (EMT), a process crucial for tissue remodeling and regeneration. During EMT, epithelial cells lose their connections to adjacent cells and acquire mesenchymal characteristics, such as migratory ability. Compared with cancer cells, normal (nontumorigenic) cells usually respond differently to TGFβ stimulation. Typically, TGFβ inhibits the proliferation of epithelial cells and may promote cell death. In cancer cells, TGFβ often promotes tumor progression. TheTGFβ-mediated induction of EMT increases cell mobility, which is associated with the formation of metastases and tumor invasion.In this work, we compared the transcriptional response of noncancerous (MCF10A) and cancerous (MCF7; estrogen receptor-positive) breast epithelial cells to direct stimulation by TGFB1 and its indirect effect through conditioned media. Some of TGFB1-induced changes, including inhibition of proliferation and induction of EMT, were similar in both cell lines. However, these changes were associated with different upstream signaling pathways. Other changes were more specific, such as disruption of estrogen-related signaling or induction of cell death in MCF7 cells. Direct incubation with TGFB1 and treatment of cells with conditioned media similarly affected target cells, indicating the presence of a bystander effect. Moreover, transcript profiling by RNA-seq revealed that the TGFβ signaling pathway is already active in untreated MCF10A cells, which may be due to their origination from a fibrotic lesion.
Sections du résumé
BACKGROUND
BACKGROUND
Transforming growth factor beta (TGFβ) is important for the morphogenesis and secretory function of the mammary gland. It is one of the main activators of the epithelial-mesenchymal transition (EMT), a process important for tissue remodeling and regeneration. It also provides cells with the plasticity to form metastases during tumor progression. Noncancerous and cancer cells respond differently to TGFβ. However, knowledge of the cellular signaling cascades triggered by TGFβ in various cell types is still limited.
METHODS
METHODS
MCF10A (noncancerous, originating from fibrotic breast tissue) and MCF7 (cancer, estrogen receptor-positive) breast epithelial cells were treated with TGFB1 directly or through conditioned media from stimulated cells. Transcriptional changes (via RNA-seq) were assessed in untreated cells and after 1-6 days of treatment. Differentially expressed genes were detected with DESeq2 and the hallmark collection was selected for gene set enrichment analysis.
RESULTS
RESULTS
TGFB1 induces EMT in both the MCF10A and MCF7 cell lines but via slightly different mechanisms (signaling through SMAD3 is more active in MCF7 cells). Many EMT-related genes are expressed in MCF10A cells at baseline. Both cell lines respond to TGFB1 by decreasing the expression of genes involved in cell proliferation: through the repression of MYC (and the protein targets) in MCF10A cells and the activation of p63-dependent signaling in MCF7 cells (CDKN1A and CDKN2B, which are responsible for the inhibition of cyclin-dependent kinases, are upregulated). In addition, estrogen receptor signaling is inhibited and caspase-dependent cell death is induced only in MCF7 cells. Direct incubation with TGFB1 and treatment of cells with conditioned media similarly affected transcriptional profiles. However, TGFB1-induced protein secretion is more pronounced in MCF10A cells; therefore, the signaling is propagated through conditioned media (bystander effect) more effectively in MCF10A cells than in MCF7 cells.
CONCLUSIONS
CONCLUSIONS
Estrogen receptor-positive breast cancer patients may benefit from high levels of TGFB1 expression due to the repression of estrogen receptor signaling, inhibition of proliferation, and induction of apoptosis in cancer cells. However, some TGFB1-stimulated cells may undergo EMT, which increases the risk of metastasis.
Transforming growth factor beta (TGFβ) is a multifaceted cytokine that controls numerous physiological and pathological processes during development and carcinogenesis. Its best-known function is the activation of epithelial–mesenchymal transition (EMT), a process crucial for tissue remodeling and regeneration. During EMT, epithelial cells lose their connections to adjacent cells and acquire mesenchymal characteristics, such as migratory ability. Compared with cancer cells, normal (nontumorigenic) cells usually respond differently to TGFβ stimulation. Typically, TGFβ inhibits the proliferation of epithelial cells and may promote cell death. In cancer cells, TGFβ often promotes tumor progression. TheTGFβ-mediated induction of EMT increases cell mobility, which is associated with the formation of metastases and tumor invasion.In this work, we compared the transcriptional response of noncancerous (MCF10A) and cancerous (MCF7; estrogen receptor-positive) breast epithelial cells to direct stimulation by TGFB1 and its indirect effect through conditioned media. Some of TGFB1-induced changes, including inhibition of proliferation and induction of EMT, were similar in both cell lines. However, these changes were associated with different upstream signaling pathways. Other changes were more specific, such as disruption of estrogen-related signaling or induction of cell death in MCF7 cells. Direct incubation with TGFB1 and treatment of cells with conditioned media similarly affected target cells, indicating the presence of a bystander effect. Moreover, transcript profiling by RNA-seq revealed that the TGFβ signaling pathway is already active in untreated MCF10A cells, which may be due to their origination from a fibrotic lesion.
Autres résumés
Type: plain-language-summary
(eng)
Transforming growth factor beta (TGFβ) is a multifaceted cytokine that controls numerous physiological and pathological processes during development and carcinogenesis. Its best-known function is the activation of epithelial–mesenchymal transition (EMT), a process crucial for tissue remodeling and regeneration. During EMT, epithelial cells lose their connections to adjacent cells and acquire mesenchymal characteristics, such as migratory ability. Compared with cancer cells, normal (nontumorigenic) cells usually respond differently to TGFβ stimulation. Typically, TGFβ inhibits the proliferation of epithelial cells and may promote cell death. In cancer cells, TGFβ often promotes tumor progression. TheTGFβ-mediated induction of EMT increases cell mobility, which is associated with the formation of metastases and tumor invasion.In this work, we compared the transcriptional response of noncancerous (MCF10A) and cancerous (MCF7; estrogen receptor-positive) breast epithelial cells to direct stimulation by TGFB1 and its indirect effect through conditioned media. Some of TGFB1-induced changes, including inhibition of proliferation and induction of EMT, were similar in both cell lines. However, these changes were associated with different upstream signaling pathways. Other changes were more specific, such as disruption of estrogen-related signaling or induction of cell death in MCF7 cells. Direct incubation with TGFB1 and treatment of cells with conditioned media similarly affected target cells, indicating the presence of a bystander effect. Moreover, transcript profiling by RNA-seq revealed that the TGFβ signaling pathway is already active in untreated MCF10A cells, which may be due to their origination from a fibrotic lesion.
Identifiants
pubmed: 39468555
doi: 10.1186/s12964-024-01821-5
pii: 10.1186/s12964-024-01821-5
doi:
Substances chimiques
Transforming Growth Factor beta1
0
TGFB1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
522Subventions
Organisme : European Social Fund Plus
ID : POWR.03.02.00-00-I029
Organisme : Narodowe Centrum Nauki
ID : 2018/29/B/ST7/02550
Informations de copyright
© 2024. The Author(s).
Références
Kahata K, Maturi V, Moustakas A. TGF-β Family Signaling in Ductal differentiation and branching morphogenesis. Cold Spring Harb Perspect Biol. 2018;10:a031997.
pubmed: 28289061
pmcid: 5830900
doi: 10.1101/cshperspect.a031997
Brenmoehl J, Ohde D, Wirthgen E, Hoeflich A. Cytokines in milk and the role of TGF-beta. Best Pract Res Clin Endocrinol Metab. 2018;32:47–56.
pubmed: 29549959
doi: 10.1016/j.beem.2018.01.006
Vander Ark A, Cao J, Li X. TGF-β receptors: in and beyond TGF-β signaling. Cell Signal. 2018;52:112–20.
pubmed: 30184463
doi: 10.1016/j.cellsig.2018.09.002
Moses H, Barcellos-Hoff MH. TGF-beta biology in mammary development and breast cancer. Cold Spring Harb Perspect Biol. 2011;3:a003277.
pubmed: 20810549
pmcid: 3003461
doi: 10.1101/cshperspect.a003277
Sundqvist A, Ten Dijke P, van Dam H. Key signaling nodes in mammary gland development and cancer: smad signal integration in epithelial cell plasticity. Breast Cancer Res. 2012;14:204.
pubmed: 22315972
pmcid: 3496114
doi: 10.1186/bcr3066
Zhang YE. Non-smad Signaling pathways of the TGF-β family. Cold Spring Harb Perspect Biol. 2017;9:a022129.
pubmed: 27864313
pmcid: 5287080
doi: 10.1101/cshperspect.a022129
Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling. Sci Signal. 2019;12:eaav5183.
pubmed: 30808818
pmcid: 6800142
doi: 10.1126/scisignal.aav5183
Wang X, Thiery JP. Harnessing Carcinoma Cell plasticity mediated by TGF-β signaling. Cancers (Basel). 2021;13:3397.
pubmed: 34298613
doi: 10.3390/cancers13143397
Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429–37.
pubmed: 19487819
pmcid: 2689132
doi: 10.1172/JCI36183
Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21:341–52.
pubmed: 32300252
pmcid: 7250738
doi: 10.1038/s41580-020-0237-9
Hao Y, Baker D, Ten Dijke P. TGF-β-Mediated epithelial-mesenchymal transition and Cancer metastasis. Int J Mol Sci. 2019;20:2767.
pubmed: 31195692
pmcid: 6600375
doi: 10.3390/ijms20112767
Noubissi Nzeteu GA, Geismann C, Arlt A, Hoogwater FJH, Nijkamp MW, Meyer NH, et al. Role of epithelial-to-mesenchymal transition for the generation of circulating tumors cells and Cancer Cell Dissemination. Cancers (Basel). 2022;14:5483.
pubmed: 36428576
doi: 10.3390/cancers14225483
Polyak K, Kalluri R. The role of the microenvironment in mammary gland development and cancer. Cold Spring Harb Perspect Biol. 2010;2:a003244.
pubmed: 20591988
pmcid: 2964182
doi: 10.1101/cshperspect.a003244
Buyuk B, Jin S, Ye K. Epithelial-to-mesenchymal transition signaling pathways responsible for breast Cancer metastasis. Cell Mol Bioeng. 2022;15:1–13.
pubmed: 35096183
doi: 10.1007/s12195-021-00694-9
Taylor MA, Parvani JG, Schiemann WP. The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. J Mammary Gland Biol Neoplasia. 2010;15:169–90.
pubmed: 20467795
pmcid: 3721368
doi: 10.1007/s10911-010-9181-1
Zarzynska JM. Two faces of TGF-beta1 in breast cancer. Mediators Inflamm. 2014;2014:141747.
pubmed: 24891760
pmcid: 4033515
doi: 10.1155/2014/141747
Wang L, Wang S, Li W. RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012;28:2184–5.
pubmed: 22743226
doi: 10.1093/bioinformatics/bts356
Babraham Bioinformatics -. FastQC A Quality Control tool for High Throughput Sequence Data [Internet]. [cited 2024 Mar 22]. https://www.bioinformatics.babraham.ac.uk/projects/fastqc/
Wingett SW, Andrews S. FastQ screen: a tool for multi-genome mapping and quality control. F1000Res. 2018;7:1338.
pubmed: 30254741
pmcid: 6124377
doi: 10.12688/f1000research.15931.1
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.
pubmed: 19505943
pmcid: 2723002
doi: 10.1093/bioinformatics/btp352
Picard Tools -. By Broad Institute [Internet]. [cited 2024 Mar 22]. https://broadinstitute.github.io/picard/
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.
pubmed: 24227677
doi: 10.1093/bioinformatics/btt656
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.
pubmed: 19910308
doi: 10.1093/bioinformatics/btp616
Love MI, Huber W, Anders S. Moderated estimation of Fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Wickham H. ggplot2: Elegant Graphics for Data Analysis [Internet]. 2nd ed. Springer International Publishing; 2016 [cited 2020 Aug 22]. https://www.springer.com/gp/book/9783319242750
Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.
pubmed: 26771021
pmcid: 4707969
doi: 10.1016/j.cels.2015.12.004
Zyla J, Marczyk M, Domaszewska T, Kaufmann SHE, Polanska J, Weiner J. Gene set enrichment for reproducible science: comparison of CERNO and eight other algorithms. Bioinformatics. 2019;35:5146–54.
pubmed: 31165139
pmcid: 6954644
doi: 10.1093/bioinformatics/btz447
Weiner J 3rd, Domaszewska T. tmod: an R package for general and multivariate enrichment analysis [Internet]. PeerJ Inc.; 2016 Sep. Report No.: e2420v1. https://peerj.com/preprints/2420
Keenan AB, Torre D, Lachmann A, Leong AK, Wojciechowicz ML, Utti V, et al. ChEA3: transcription factor enrichment analysis by orthogonal omics integration. Nucleic Acids Res. 2019;47:W212–24.
pubmed: 31114921
pmcid: 6602523
doi: 10.1093/nar/gkz446
Luo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics. 2013;29:1830–1.
pubmed: 23740750
pmcid: 3702256
doi: 10.1093/bioinformatics/btt285
Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.
pubmed: 10655586
doi: 10.1038/35000025
Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–9.
pubmed: 10655587
doi: 10.1038/35000034
Bolós V, Peinado H, Pérez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with snail and E47 repressors. J Cell Sci. 2003;116:499–511.
pubmed: 12508111
doi: 10.1242/jcs.00224
Chen CR, Kang Y, Massagué J. Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor beta growth arrest program. Proc Natl Acad Sci U S A. 2001;98:992–9.
pubmed: 11158583
pmcid: 14697
doi: 10.1073/pnas.98.3.992
Kang Y, Chen C-R, Massagué J. A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell. 2003;11:915–26.
pubmed: 12718878
doi: 10.1016/S1097-2765(03)00109-6
Vydra N, Janus P, Kus P, Stokowy T, Mrowiec K, Toma-Jonik A, et al. Heat shock factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells. Elife. 2021;10:e69843.
pubmed: 34783649
pmcid: 8709578
doi: 10.7554/eLife.69843
Győrffy B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Comput Struct Biotechnol J. 2021;19:4101–9.
pubmed: 34527184
pmcid: 8339292
doi: 10.1016/j.csbj.2021.07.014
Zhang Y, Alexander PB, Wang X-F. TGF-β Family Signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol. 2017;9:a022145.
pubmed: 27920038
pmcid: 5378054
doi: 10.1101/cshperspect.a022145
Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A. 1995;92:5545–9.
pubmed: 7777546
pmcid: 41732
doi: 10.1073/pnas.92.12.5545
Li CY, Suardet L, Little JB. Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect. J Biol Chem. 1995;270:4971–4.
pubmed: 7890601
doi: 10.1074/jbc.270.10.4971
Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371:257–61.
pubmed: 8078588
doi: 10.1038/371257a0
Reynisdóttir I, Polyak K, Iavarone A, Massagué J. Kip/Cip and Ink4 cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev. 1995;9:1831–45.
pubmed: 7649471
doi: 10.1101/gad.9.15.1831
Piezzo M, Cocco S, Caputo R, Cianniello D, Gioia GD, Lauro VD, et al. Targeting cell cycle in breast Cancer: CDK4/6 inhibitors. Int J Mol Sci. 2020;21:6479.
pubmed: 32899866
pmcid: 7554788
doi: 10.3390/ijms21186479
Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ. 2022;29:946–60.
pubmed: 35361964
pmcid: 9090780
doi: 10.1038/s41418-022-00988-z
Dohn M, Zhang S, Chen X. p63alpha and DeltaNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes. Oncogene. 2001;20:3193–205.
pubmed: 11423969
doi: 10.1038/sj.onc.1204427
Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M. Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology. 2010;52:966–74.
pubmed: 20583212
doi: 10.1002/hep.23769
Tominaga K, Suzuki HI. TGF-β signaling in Cellular Senescence and Aging-Related Pathology. Int J Mol Sci. 2019;20:5002.
pubmed: 31658594
pmcid: 6834140
doi: 10.3390/ijms20205002
Lee AV, Oesterreich S, Davidson NE. MCF-7 cells–changing the course of breast cancer research and care for 45 years. J Natl Cancer Inst. 2015;107:djv073.
pubmed: 25828948
doi: 10.1093/jnci/djv073
Ramesh S, Wildey GM, Howe PH. Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim. Cell Cycle. 2009;8:11–7.
pubmed: 19106608
doi: 10.4161/cc.8.1.7291
Ramjaun AR, Tomlinson S, Eddaoudi A, Downward J. Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene. 2007;26:970–81.
pubmed: 16909112
doi: 10.1038/sj.onc.1209852
Schuster N, Krieglstein K. Mechanisms of TGF-beta-mediated apoptosis. Cell Tissue Res. 2002;307:1–14.
pubmed: 11810309
doi: 10.1007/s00441-001-0479-6
Li Q, Wu L, Oelschlager DK, Wan M, Stockard CR, Grizzle WE, et al. Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells. J Biol Chem. 2005;280:27022–8.
pubmed: 15886208
doi: 10.1074/jbc.M505071200
Zhang J, Tian X-J, Zhang H, Teng Y, Li R, Bai F, et al. TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal. 2014;7:ra91.
pubmed: 25270257
doi: 10.1126/scisignal.2005304
Antón-García P, Haghighi EB, Rose K, Vladimirov G, Boerries M, Hecht A. TGFβ1-Induced EMT in the MCF10A mammary epithelial cell line model is executed independently of SNAIL1 and ZEB1 but relies on JUNB-Coordinated Transcriptional Regulation. Cancers (Basel). 2023;15:558.
pubmed: 36672507
doi: 10.3390/cancers15020558
Deshmukh AP, Vasaikar SV, Tomczak K, Tripathi S, den Hollander P, Arslan E, et al. Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc Natl Acad Sci U S A. 2021;118:e2102050118.
pubmed: 33941680
pmcid: 8126782
doi: 10.1073/pnas.2102050118
Paul I, Bolzan D, Youssef A, Gagnon KA, Hook H, Karemore G, et al. Parallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT. Nat Commun. 2023;14:688.
pubmed: 36755019
pmcid: 9908882
doi: 10.1038/s41467-023-36122-x
Wagner J, Masek M, Jacobs A, Soneson C, Sivapatham S, Damond N, et al. Mass cytometric and transcriptomic profiling of epithelial-mesenchymal transitions in human mammary cell lines. Sci Data. 2022;9:44.
pubmed: 35140234
pmcid: 8828897
doi: 10.1038/s41597-022-01137-4
Puleo J, Polyak K. The MCF10 model of breast tumor progression. Cancer Res. 2021;81:4183–5.
pubmed: 34400468
doi: 10.1158/0008-5472.CAN-21-1939
Qu Y, Han B, Yu Y, Yao W, Bose S, Karlan BY, et al. Evaluation of MCF10A as a Reliable Model for Normal Human Mammary epithelial cells. PLoS ONE. 2015;10:e0131285.
pubmed: 26147507
pmcid: 4493126
doi: 10.1371/journal.pone.0131285
Bouris P, Skandalis SS, Piperigkou Z, Afratis N, Karamanou K, Aletras AJ, et al. Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biol. 2015;43:42–60.
pubmed: 25728938
doi: 10.1016/j.matbio.2015.02.008
Gao Y, Wang Z, Hao Q, Li W, Xu Y, Zhang J, et al. Loss of ERα induces amoeboid-like migration of breast cancer cells by downregulating vinculin. Nat Commun. 2017;8:14483.
pubmed: 28266545
pmcid: 5344302
doi: 10.1038/ncomms14483
Cheng JN, Frye JB, Whitman SA, Kunihiro AG, Pandey R, Funk JL. A role for TGFβ signaling in Preclinical Osteolytic Estrogen receptor-positive breast Cancer Bone metastases Progression. Int J Mol Sci. 2021;22:4463.
pubmed: 33923316
pmcid: 8123146
doi: 10.3390/ijms22094463
Zhao Y, Ma J, Fan Y, Wang Z, Tian R, Ji W, et al. TGF-β transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways. Mol Oncol. 2018;12:305–21.
pubmed: 29215776
pmcid: 5830653
doi: 10.1002/1878-0261.12162
Sundqvist A, Vasilaki E, Voytyuk O, Bai Y, Morikawa M, Moustakas A, et al. TGFβ and EGF signaling orchestrates the AP-1- and p63 transcriptional regulation of breast cancer invasiveness. Oncogene. 2020;39:4436–49.
pubmed: 32350443
pmcid: 7253358
doi: 10.1038/s41388-020-1299-z
Malek D, Gust R, Kleuser B. 17-Beta-estradiol inhibits transforming-growth-factor-beta-induced MCF-7 cell migration by Smad3-repression. Eur J Pharmacol. 2006;534:39–47.
pubmed: 16497293
doi: 10.1016/j.ejphar.2006.01.025
Cherlet T, Murphy LC. Estrogen receptors inhibit Smad3 transcriptional activity through Ap-1 transcription factors. Mol Cell Biochem. 2007;306:33–42.
pubmed: 17660955
doi: 10.1007/s11010-007-9551-1
Ito I, Hanyu A, Wayama M, Goto N, Katsuno Y, Kawasaki S, et al. Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation. J Biol Chem. 2010;285:14747–55.
pubmed: 20207742
pmcid: 2863224
doi: 10.1074/jbc.M109.093039
Band AM, Laiho M. Crosstalk of TGF-β and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2011;16:109–15.
pubmed: 21390570
doi: 10.1007/s10911-011-9203-7
Jayaraman L, Massague J. Distinct oligomeric states of SMAD proteins in the transforming growth factor-beta pathway. J Biol Chem. 2000;275:40710–7.
pubmed: 11018029
doi: 10.1074/jbc.M005799200
Inman GJ, Hill CS. Stoichiometry of active smad-transcription factor complexes on DNA. J Biol Chem. 2002;277:51008–16.
pubmed: 12374795
doi: 10.1074/jbc.M208532200
Brown KA, Pietenpol JA, Moses HL. A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem. 2007;101:9–33.
pubmed: 17340614
doi: 10.1002/jcb.21255
Inman GJ. Linking smads and transcriptional activation. Biochem J. 2005;386:e1–3.
pubmed: 15702493
pmcid: 1134782
doi: 10.1042/BJ20042133
Chen H, Tritton TR, Kenny N, Absher M, Chiu JF. Tamoxifen induces TGF-beta 1 activity and apoptosis of human MCF-7 breast cancer cells in vitro. J Cell Biochem. 1996;61:9–17.
pubmed: 8726350
doi: 10.1002/(SICI)1097-4644(19960401)61:1<9::AID-JCB2>3.0.CO;2-Z
Farhood B, Khodamoradi E, Hoseini-Ghahfarokhi M, Motevaseli E, Mirtavoos-Mahyari H, Eleojo Musa A, et al. TGF-β in radiotherapy: mechanisms of tumor resistance and normal tissues injury. Pharmacol Res. 2020;155:104745.
pubmed: 32145401
doi: 10.1016/j.phrs.2020.104745
Czekay R-P, Cheon D-J, Samarakoon R, Kutz SM, Higgins PJ. Cancer-Associated fibroblasts: mechanisms of Tumor Progression and Novel therapeutic targets. Cancers (Basel). 2022;14:1231.
pubmed: 35267539
doi: 10.3390/cancers14051231
Pang M-F, Georgoudaki A-M, Lambut L, Johansson J, Tabor V, Hagikura K, et al. TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis. Oncogene. 2016;35:748–60.
pubmed: 25961925
doi: 10.1038/onc.2015.133
Azzarito G, Visentin M, Leeners B, Dubey RK. Transcriptomic and functional evidence for Differential effects of MCF-7 breast Cancer cell-secretome on vascular and lymphatic endothelial cell growth. Int J Mol Sci. 2022;23:7192.
pubmed: 35806196
pmcid: 9266834
doi: 10.3390/ijms23137192
Culig Z. Epithelial mesenchymal transition and resistance in endocrine-related cancers. Biochim Biophys Acta Mol Cell Res. 2019;1866:1368–75.
pubmed: 31108117
doi: 10.1016/j.bbamcr.2019.05.003
Gómez-Gil V. Therapeutic implications of TGFβ in Cancer Treatment: a systematic review. Cancers (Basel). 2021;13:379.
pubmed: 33498521
doi: 10.3390/cancers13030379
Desruisseau S, Palmari J, Giusti C, Romain S, Martin P-M, Berthois Y. Determination of TGFbeta1 protein level in human primary breast cancers and its relationship with survival. Br J Cancer. 2006;94:239–46.
pubmed: 16404434
pmcid: 2361106
doi: 10.1038/sj.bjc.6602920
Panis C, Herrera AC, Victorino VJ, Aranome AMF, Cecchini R. Screening of circulating TGF-β levels and its clinicopathological significance in human breast cancer. Anticancer Res. 2013;33:737–42.
pubmed: 23393376
Ciftci R, Tas F, Yasasever CT, Aksit E, Karabulut S, Sen F, et al. High serum transforming growth factor beta 1 (TGFB1) level predicts better survival in breast cancer. Tumour Biol. 2014;35:6941–8.
pubmed: 24740564
doi: 10.1007/s13277-014-1932-y