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Journal of Mammary Gland Biology and Neoplasia
Published in: Journal of Mammary Gland Biology and Neoplasia 2/2011

01-06-2011

Crosstalk of TGF-β and Estrogen Receptor Signaling in Breast Cancer

Authors: Arja M. Band, Marikki Laiho

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 2/2011

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Abstract

Estrogen receptor-α (ERα) and transforming growth factor (TGF)-β signaling pathways are major regulators during mammary gland development, function and tumorigenesis. Predominantly, they have opposing roles in proliferation and apoptosis. While ERα signaling supports growth and differentiation and is antiapoptotic, mammary gland epithelia cells are very sensitive to TGF-β—induced cell cycle arrest and apoptosis. Their regulatory pathways intersect, and ERα blocks TGF-β pathway by multiple means, including direct interactions of its signaling components, Smads. However, relatively little is known of the dysfunction of their interactions in cancer. A better understanding would help to develop new strategies for breast cancer treatment.
Literature
1.
Bocchinfuso WP, Korach KS. Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia. 1997;2:323–34.PubMedCrossRef
2.
Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999;20:358–417.PubMedCrossRef
3.
Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996;93:5925–30.PubMedCrossRef
4.
Hall JM, McDonnell DP. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology. 1999;140:5566–78.PubMedCrossRef
5.
Mak P, Leav I, Pursell B, Bae D, Yang X, Taglienti CA, et al. ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell. 2010;17:319–32.PubMedCrossRef
6.
Palmieri C, Saji S, Sakaguchi H, Cheng G, Sunters A, O'Hare MJ, et al. The expression of oestrogen receptor (ER)-beta and its variants, but not ERalpha, in adult human mammary fibroblasts. J Mol Endocrinol. 2004;33:35–50.PubMedCrossRef
7.
Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci U S A. 1998;95:15677–82.PubMedCrossRef
8.
Ogawa S, Chan J, Chester AE, Gustafsson JA, Korach KS, Pfaff DW. Survival of reproductive behaviors in estrogen receptor beta gene-deficient (betaERKO) male and female mice. Proc Natl Acad Sci U S A. 1999;96:12887–92.PubMedCrossRef
9.
10.
Clarke RB, Howell A, Potten CS, Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 1997;57:4987–91.PubMed
11.
Dubik D, Dembinski TC, Shiu RP. Stimulation of c-myc oncogene expression associated with estrogen-induced proliferation of human breast cancer cells. Cancer Res. 1987;47:6517–21.PubMed
12.
Musgrove EA, Lee CS, Buckley MF, Sutherland RL. Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci U S A. 1994;91:8022–6.PubMedCrossRef
13.
Butt AJ, McNeil CM, Musgrove EA, Sutherland RL. Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer. 2005;12:S47–59. PubMedCrossRef
14.
Lewis-Wambi JS, Jordan VC. Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res. 2009;11:206.PubMedCrossRef
15.
Donovan J, Slingerland J. Transforming growth factor-beta and breast cancer: cell cycle arrest by transforming growth factor-beta and its disruption in cancer. Breast Cancer Res. 2000;2:116–24.PubMedCrossRef
16.
Heldin CH, Landström M, Moustakas A. Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol. 2009;21:166–76.PubMedCrossRef
17.
Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007;8:970–82.PubMedCrossRef
18.
Lönn P, Morén A, Raja E, Dahl M, Moustakas A. Regulating the stability of TGFbeta receptors and Smads. Cell Res. 2009;19:21–35.PubMedCrossRef
19.
Luo K. Ski and SnoN: negative regulators of TGF-beta signaling. Curr Opin Genet Dev. 2004;14:65–70.PubMedCrossRef
20.
Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89:1165–73.PubMedCrossRef
21.
Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell. 2000;6:1365–75.PubMedCrossRef
22.
Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276:12477–80.PubMedCrossRef
23.
Shi W, Sun C, He B, Xiong W, Shi X, Yao D, et al. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol. 2004;164:291–300.PubMedCrossRef
24.
Zhang S, Fei T, Zhang L, Zhang R, Chen F, Ning Y, et al. Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol Cell Biol. 2007;27:4488–99.PubMedCrossRef
25.
Sun Y, Liu X, Ng-Eaton E, Lodish HF, Weinberg RA. SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. Proc Natl Acad Sci U S A. 1999;96:12442–7.PubMedCrossRef
26.
Bonni S, Wang HR, Causing CG, Kavsak P, Stroschein SL, Luo K, et al. TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol. 2001;3:587–95.PubMedCrossRef
27.
Stroschein SL, Bonni S, Wrana JL, Luo K. Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Genes Dev. 2001;15:2822–36.PubMed
28.
Wan Y, Liu X, Kirschner MW. The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Mol Cell. 2001;8:1027–39.PubMedCrossRef
29.
Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill CS. Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Mol Cell Biol. 2007;27:6068–83.PubMedCrossRef
30.
Band A, Laiho M. Proteasome in the control of TGF-β signaling during development and cancer. In Jakowlew S, editor. Transforming growth factor-beta in cancer therapy. Totowa, New Jersey; Humana Press; 2008. pp. 243–57.
31.
Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science. 1999;286:771–4.PubMedCrossRef
32.
Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, et al. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev. 1999;13:2196–206.PubMedCrossRef
33.
Nomura T, Khan MM, Kaul SC, Dong HD, Wadhwa R, Colmenares C, et al. Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor. Genes Dev. 1999;13:412–23.PubMedCrossRef
34.
Suzuki H, Yagi K, Kondo M, Kato M, Miyazono K, Miyazawa K. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements. Oncogene. 2004;23:5068–76.PubMedCrossRef
35.
Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, et al. Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling. J Biol Chem. 2007;282:20492–501.PubMedCrossRef
36.
Le Scolan E, Zhu Q, Wang L, Bandyopadhyay A, Javelaud D, Mauviel A, et al. Transforming growth factor-beta suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation. Cancer Res. 2008;68:3277–85.PubMedCrossRef
37.
38.
Tabata T, Kokura K, Ten Dijke P, Ishii S. Ski co-repressor complexes maintain the basal repressed state of the TGF-beta target gene, SMAD7, via HDAC3 and PRMT5. Genes Cells. 2009;14:17–28.PubMedCrossRef
39.
Band AM, Björklund M, Laiho M. The phosphatidylinositol 3-kinase/Akt pathway regulates transforming growth factor-beta signaling by destabilizing ski and inducing Smad7. J Biol Chem. 2009;284:35441–9.PubMedCrossRef
40.
41.
Hall JM, McDonnell DP. Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv. 2005;5:343–57.PubMedCrossRef
42.
Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997;389:753–8.PubMedCrossRef
43.
Cheskis BJ, Greger JG, Nagpal S, Freedman LP. Signaling by estrogens. J Cell Physiol. 2007;213:610–7.PubMedCrossRef
44.
Métivier R, Penot G, Hübner MR, Reid G, Brand H, Kos M, et al. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell. 2003;115:751–63.PubMedCrossRef
45.
Heery DM, Kalkhoven E, Hoare S, Parker MG, Heery DM, Kalkhoven E, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997;387:733–6.PubMedCrossRef
46.
Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature. 1997;387:677–84.PubMedCrossRef
47.
Vega VB, Lin CY, Lai KS, Kong SL, Xie M, Su X, et al. Multiplatform genome-wide identification and modeling of functional human estrogen receptor binding sites. Genome Biol. 2006;7:R82.PubMedCrossRef
48.
Lin CY, Vega VB, Thomsen JS, Zhang T, Kong SL, Xie M, et al. Whole-genome cartography of estrogen receptor alpha binding sites. PLoS Genet. 2007;3:e87.PubMedCrossRef
49.
Stender JD, Kim K, Charn TH, Komm B, Chang KC, Kraus WL, et al. Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. Mol Cell Biol. 2010;30:3943–55.PubMedCrossRef
50.
Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet. 2011;43:27–33.PubMedCrossRef
51.
Le Goff P, Montano MM, Schodin DJ, Katzenellenbogen BS. Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem. 1994;269:4458–66.PubMed
52.
Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995;270:1491–4.PubMedCrossRef
53.
Trowbridge JM, Rogatsky I, Garabedian MJ. Regulation of estrogen receptor transcriptional enhancement by the cyclin A/Cdk2 complex. Proc Natl Acad Sci U S A. 1997;94:10132–7.PubMedCrossRef
54.
Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, et al. Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. J Biol Chem. 2001;276:18375–83.PubMedCrossRef
55.
Cui Y, Zhang M, Pestell R, Curran EM, Welshons WV, Fuqua SA. Phosphorylation of estrogen receptor alpha blocks its acetylation and regulates estrogen sensitivity. Cancer Res. 2004;64:9199–208.PubMedCrossRef
56.
Kim MY, Woo EM, Chong YT, Homenko DR, Kraus WL. Acetylation of estrogen receptor alpha by p300 at lysines 266 and 268 enhances the deoxyribonucleic acid binding and transactivation activities of the receptor. Mol Endocrinol. 2006;20:1479–93.PubMedCrossRef
57.
Subramanian K, Jia D, Kapoor-Vazirani P, Powell DR, Collins RE, Sharma D, et al. Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase. Mol Cell. 2008;30:336–47.PubMedCrossRef
58.
59.
Ewan KB, Oketch-Rabah HA, Ravani SA, Shyamala G, Moses HL, Barcellos-Hoff MH, et al. Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice. Am J Pathol. 2005;167:409–17.PubMedCrossRef
60.
Matsuda T, Yamamoto T, Muraguchi A, Saatcioglu F. Cross-talk between transforming growth factor-beta and estrogen receptor signaling through Smad3. J Biol Chem. 2001;276:42908–14.PubMedCrossRef
61.
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.PubMedCrossRef
62.
Cherlet T, Murphy LC. Estrogen receptors inhibit Smad3 transcriptional activity through Ap-1 transcription factors. Mol Cell Biochem. 2007;306:33–42.PubMedCrossRef
63.
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.PubMedCrossRef
64.
Burdette JE, Woodruff TK. Activin and estrogen crosstalk regulates transcription in human breast cancer cells. Endocr Relat Cancer. 2007;14:679–89.PubMedCrossRef
65.
Dhasarathy A, Kajita M, Wade PA. The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Mol Endocrinol. 2007;21:2907–18.PubMedCrossRef
66.
Buck MB, Pfizenmaier K, Knabbe C. Antiestrogens induce growth inhibition by sequential activation of p38 mitogen-activated protein kinase and transforming growth factor-beta pathways in human breast cancer cells. Mol Endocrinol. 2004;18:1643–57.PubMedCrossRef
67.
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.PubMedCrossRef
68.
69.
Bierie B, Moses HL. Gain or loss of TGFbeta signaling in mammary carcinoma cells can promote metastasis. Cell Cycle. 2009;8:3319–27.PubMedCrossRef
70.
Bierie B, Chung CH, Parker JS, Stover DG, Cheng N, Chytil A, et al. Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest. 2009;119:1571–82.PubMedCrossRef
71.
Joffroy CM, Buck MB, Stope MB, Popp SL, Pfizenmaier K, Knabbe C. Antiestrogens induce transforming growth factor beta-mediated immunosuppression in breast cancer. Cancer Res. 2010;70:1314–22.PubMedCrossRef
72.
Wu L, Wu Y, Gathings B, Wan M, Li X, Grizzle W, et al. Smad4 as a transcription corepressor for estrogen receptor alpha. J Biol Chem. 2003;278:15192–200.PubMedCrossRef
73.
Ren Y, Wu L, Frost AR, Grizzle W, Cao X, Wan M. Dual effects of TGF-beta on ERalpha-mediated estrogenic transcriptional activity in breast cancer. Mol Cancer. 2009;8:111.PubMedCrossRef
74.
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.PubMedCrossRef
75.
Deheuninck J, Luo K. Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Res. 2009;19:47–57.PubMedCrossRef
76.
Jahchan NS, Luo K. SnoN in mammalian development, function and diseases. Curr Opin Pharmacol. 2010;10:670–5.PubMedCrossRef
77.
Edmiston JS, Yeudall WA, Chung TD, Lebman DA. Inability of transforming growth factor-beta to cause SnoN degradation leads to resistance to transforming growth factor-beta-induced growth arrest in esophageal cancer cells. Cancer Res. 2005;65:4782–8.PubMedCrossRef
78.
Zhang F, Lundin M, Ristimäki A, Heikkilä P, Lundin J, Isola J, et al. Ski-related novel protein N (SnoN), a negative controller of transforming growth factor-beta signaling, is a prognostic marker in estrogen receptor-positive breast carcinomas. Cancer Res. 2003;63:5005–10.PubMed
79.
Zhu Q, Krakowski AR, Dunham EE, Wang L, Bandyopadhyay A, Berdeaux R, et al. Dual role of SnoN in mammalian tumorigenesis. Mol Cell Biol. 2007;27:324–39.PubMedCrossRef
80.
Jahchan NS, You YH, Muller WJ, Luo K. Transforming growth factor-beta regulator SnoN modulates mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis. Cancer Res. 2010;70:4204–13.PubMedCrossRef
81.
Shinagawa T, Dong HD, Xu M, Maekawa T, Ishii S. The sno gene, which encodes a component of the histone deacetylase complex, acts as a tumor suppressor in mice. EMBO J. 2000;19:2280–91.PubMedCrossRef
Metadata
Title
Crosstalk of TGF-β and Estrogen Receptor Signaling in Breast Cancer
Authors
Arja M. Band
Marikki Laiho
Publication date
01-06-2011
Publisher
Springer US
Published in
Journal of Mammary Gland Biology and Neoplasia / Issue 2/2011
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI
https://doi.org/10.1007/s10911-011-9203-7

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