The TGFβ2-Snail1-miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer

Liyun Luo , Ning Xu , Weina Fan , Yixuan Wu , Pingping Chen , Zhihui Li , Zhimin He , Hao Liu , Ying Lin , Guopei Zheng

Clinical and Translational Medicine ›› 2024, Vol. 14 ›› Issue (2) : e1558

PDF
Clinical and Translational Medicine ›› 2024, Vol. 14 ›› Issue (2) : e1558 DOI: 10.1002/ctm2.1558
RESEARCH ARTICLE

The TGFβ2-Snail1-miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer

Author information +
History +
PDF

Abstract

There have been contradictory reports on the biological role of transforming growth factor-βs (TGFβs) in breast cancer (BC), especially with regard to their ability to promote epithelial-mesenchymal transition (EMT). Here, we show that TGFβ2 is preferentially expressed in mesenchymal-like BCs and maintains the EMT phenotype, correlating with cancer stem cell-like characteristics, growth, metastasis and chemo-resistance and predicting worse clinical outcomes. However, this is only true in ERα BC. In ERα+ luminal-type BC, estrogen receptor interacts with p-Smads to block TGFβ signalling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFβ2) that is weakened in TGFβ2-overexpressing BC cells. We discover that TGFβ2-Snail1 recruits enhancer of zeste homolog-2 to convert miRNAsTGFβ2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFβ2 overexpression reverses the mesenchymal-like traits in agreement with the inhibition of TGFβ2-Snail1 signalling in BC cells. These findings clarify the roles of TGFβ2 in BC and suggest novel therapeutic strategies based on the TGFβ2-Snail1-miRNAsTGFβ2 loop for a subset type of human BCs.

Keywords

breast cancer / chromatin configuration / epithelial-mesenchymal transition / miRNAs / TGFβ2

Cite this article

Download citation ▾
Liyun Luo, Ning Xu, Weina Fan, Yixuan Wu, Pingping Chen, Zhihui Li, Zhimin He, Hao Liu, Ying Lin, Guopei Zheng. The TGFβ2-Snail1-miRNATGFβ2 Circuitry is Critical for the Development of Aggressive Functions in Breast Cancer. Clinical and Translational Medicine, 2024, 14(2): e1558 DOI:10.1002/ctm2.1558

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Bertos NR, Park M. Breast cancer—one term, many entities?J Clin Invest. 2011;121(10):3789-3796.

[2]

Polyak K, Shipitsin M, Campbell-Marrotta LL, Bloushtain-Qimron N, Park SY. Breast tumor heterogeneity: causes and consequences. Breast Cancer Res. 2009;11:S18.

[3]

Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747-752.

[4]

Vargo-Gogola T, Rosen JM. Modelling breast cancer: one size does not fit all. Nat Rev Cancer. 2007;7(9):659-762.

[5]

Badve S, Dabbs DJ, Schnitt SJ, et al. Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol. 2011;24(2):157-167.

[6]

Fadare O, Tavassoli FA. Clinical and pathologic aspects of basal-like breast cancers. Nat Clin Pract Oncol. 2008;5(3):149-159.

[7]

Korsching E, Jeffrey SS, Meinerz W, Decker T, Boecker W, Buerger H. Basal carcinoma of the breast revisited: an old entity with new interpretations. J Clin Pathol. 2008;61(5):553-560.

[8]

Kreike B, Kouwenhove M, Horlings H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007;9(5):R65.

[9]

Rakha EA, Reis-Filho JS, IO E. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26(15):2568-2581.

[10]

Drasin DJ, Robin TP, Ford HL. Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity. Breast Cancer Res. 2011;13(6):226.

[11]

Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15(2):117-134.

[12]

Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265-273.

[13]

Thiery JP, Acloque H, Huang RYJ, Angela Nieto M. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871-890.

[14]

Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27(20):2192-2206.

[15]

Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818-829.

[16]

Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820-13825.

[17]

Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679.

[18]

Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704-1515.

[19]

Moody SE, Perez D, Pan TC, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 2005;8(3):197-209.

[20]

Aktas B, Tewes M, Fehm T, et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009;11(4):R46.

[21]

Armstrong AJ, Marengo MS, Oltean S, et al. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res. 2011;9(8):997-1007.

[22]

Bonnomet A, Brysse A, Tachsidis A, et al. Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia. 2010;15(2):261-273.

[23]

Kallergi G, Papadaki MA, Politaki E, et al. Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res. 2011;13(3):R59.

[24]

Kasimir-Bauer S, Hoffmann O, Wallwiener D, Kimmig R, Fehm T. Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res. 2012;14(1):R15.

[25]

Lu J, Fan T, Zhao Q, et al. Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int J Cancer. 2010;126(3):669-683.

[26]

Mego M, Mani SA, Lee B-N, et al. Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy. Int J Cancer. 2012;130(4):808-816.

[27]

Raimondi C, Gradilone A, Naso G, et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat. 2011;130(2):449-455.

[28]

Yu M, Bardia A, Wittner BS, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580-584.

[29]

Massagué J, TGFbeta in cancer. Cell. 2008;134(2):215-2130.

[30]

Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10(6):415-424.

[31]

Attisano L, Wrana JL. Signal transduction by the TGF-beta superfamily. Science. 2002;296(5573):1646-1647.

[32]

Gavert N, Ben-Ze'ev A. Epithelial-mesenchymal transition and the invasive potential of tumors. Trends Mol Med. 2008;14(5):199-209.

[33]

Hernández-Vega AM, Camacho-Arroyo I. Crosstalk between 17β-Estradiol and TGFβ signaling modulates glioblastoma progression. Brain Sci. 2021;11(5):564.

[34]

Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res. 2014;33(1):62.

[35]

Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004;24(17):7559-7566.

[36]

Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704-715.

[37]

Vincent T, Neve EPA, Johnson JR, et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009;11(8):943-950.

[38]

Brown KA, Aakre ME, Gorska AE, et al. Induction by transforming growth factor-beta1 of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res. 2004;6(3):R215-231.

[39]

Lin X-J, Chong Y, Guo Z-W, et al. A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. The Lancet Oncology. 2015;16(7):804-815.

[40]

Ciszewski WM, Sobierajska K, Wawro ME, et al. The ILK-MMP9-MRTF axis is crucial for EndMT differentiation of endothelial cells in a tumor microenvironment. Biochim Biophys Acta Mol Cell Res. 2017;1864(12):2283-2296.

[41]

Maleszewska M, Moonen J-RAJ, Huijkman N, et al. IL-1beta and TGFbeta2 synergistically induce endothelial to mesenchymal transition in an NFkappaB-dependent manner. Immunobiology. 2013;218(4):443-454.

[42]

Chen L, Peng Z, Meng Q, et al. Loss of IkappaB kinase beta promotes myofibroblast transformation and senescence through activation of the ROS-TGFbeta autocrine loop. Protein Cell. 2016;7(5):338-350.

[43]

Insua-Rodríguez J, Oskarsson T. The extracellular matrix in breast cancer. Adv Drug Deliv Rev. 2016;97:41-55.

[44]

Padua D, Zhang XH-F, Wang Q, et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008;133(1):66-77.

[45]

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215-233.

[46]

Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10(10):704-714.

[47]

Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009;11(9):1143-1149.

[48]

Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513-10518.

[49]

Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593-601.

[50]

Zhao G, Wang Bo, Liu Y, et al. miRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4. Mol Cancer Ther. 2013;12(11):2569-2580.

[51]

Chen X, Wang X, Ruan A, et al. miR-141 is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression. Clin Cancer Res. 2014;20(10):2617-2630.

[52]

Dong Su, Meng X, Xue S, et al. microRNA-141 inhibits thyroid cancer cell growth and metastasis by targeting insulin receptor substrate 2. Am J Transl Res. 2016;8(3):1471-1481.

[53]

Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22(7):894-907.

[54]

Tsouko E, Wang J, Frigo DE, Aydoğdu E, Williams C. miR-200a inhibits migration of triple-negative breast cancer cells through direct repression of the EPHA2 oncogene. Carcinogenesis. 2015;36(9):1051-1060.

[55]

Sachdeva M, Mo YY. MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res. 2010;70(1):378-387.

[56]

Spizzo R, Nicoloso MS, Lupini L, et al. miR-145 participates with TP53 in a death-promoting regulatory loop and targets estrogen receptor-alpha in human breast cancer cells. Cell Death Differ. 2010;17(2):246-254.

[57]

Xu Na, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 2009;137(4):647-658.

[58]

Morgado AL, Rodrigues CMP, Solá S. MicroRNA-145 regulates neural stem cell differentiation through the Sox2-Lin28/let-7 signaling pathway. Stem Cells. 2016;34(5):1386-1395.

[59]

Mateescu B, Batista L, Cardon M, et al. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med. 2011;17(12):1627-1635.

[60]

T M van Jaarsveld M, Helleman J, Boersma AWM, et al. miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells. Oncogene. 2013;32(36):4284-4293.

[61]

Dong C, Yuan T, Wu Y, et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 2013;23(3):316-331.

[62]

Dong C, Wu Y, Yao J, et al. G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer. J Clin Invest. 2012;122(4):1469-1486.

[63]

Soleimani VD, Yin H, Jahani-Asl A, et al. Snail regulates MyoD binding-site occupancy to direct enhancer switching and differentiation-specific transcription in myogenesis. Molecular cell. 2012;47(3):457-468.

[64]

Zhang X, Zhao X, Fiskus W, et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell. 2012;22(4):506-523.

[65]

Yamagishi M, Nakano K, Miyake A, et al. Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kappaB pathway in adult T cell leukemia and other cancers. Cancer Cell. 2012;21(1):121-135.

[66]

Kottakis F, Polytarchou C, Foltopoulou P, et al. FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol Cell. 2011;43(2):285-298.

[67]

Ito I, Hanyu A, Wayama M, et al. Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation. J Biol Chem. 2010;285(19):14747-14755.

[68]

Wu L, Wu Y, Gathings B, et al. Smad4 as a transcription corepressor for estrogen receptor alpha. J Biol Chem. 2003;278(17):15192-15200.

[69]

García-Becerra R, Santos N, Díaz L, Camacho J. Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance. Int J Mol Sci. 2012;14(1):108-145.

[70]

Xu Y, Lee D-K, Feng Z, et al. Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice. Proc Natl Acad Sci U S A. 2017;114(43):11494-11499.

[71]

Bernardo GM, Lozada KL, Miedler JD, et al. FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis. Development. 2010;137(12):2045-2054.

[72]

Guttilla IK, Adams BD, White BA. ERalpha, microRNAs, and the epithelial-mesenchymal transition in breast cancer. Trends Endocrinol Metab. 2012;23(2):73-82.

[73]

Bui QT, Im JH, Jeong SB, et al. Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer. Cancer Lett. 2017;390:115-125.

[74]

Tilghman SL, Townley I, Zhong Q, et al. Proteomic signatures of acquired letrozole resistance in breast cancer: suppressed estrogen signaling and increased cell motility and invasiveness. Mol Cell Proteomics. 2013;12(9):2440-2455.

RIGHTS & PERMISSIONS

2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

AI Summary AI Mindmap
PDF

162

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/