Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2009

Open Access 01-12-2009 | Research

Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer

Authors: Yongsheng Ren, Liyu Wu, Andra R Frost, William Grizzle, Xu Cao, Mei Wan

Published in: Molecular Cancer | Issue 1/2009

Login to get access

Abstract

Background

TGF-β resistance often develops in breast cancer cells that in turn overproduce this cytokine to create a local immunosuppressive environment that fosters tumor growth and exacerbates the invasive and metastatic behavior of the tumor cells themselves. Smads-mediated cross-talk with the estrogen receptor has been implied to play an important role in development and/or progression of breast cancer. We investigated how TGF-β regulates ERα-induced gene transcription and potential mechanisms of frequent TGF-β resistance in breast cancer.

Methods

Effect of TGF-β on ERα-mediated gene transcription was investigated in breast cancer cell lines using transient transfection, real-time PCR, sequential DNA precipitation, and small interfering RNA assays. The expression of Smads on both human breast cancer cell lines and ERα-positive human breast cancer tissue was evaluated by immunofluorescence and immunohistochemical assays.

Results

A complex of Smad3/4 mediates TGF-β inhibition of ERα-mediated estrogenic activity of gene transcription in breast cancer cells, and Smad4 is essential and sufficient for such repression. Either overexpression of Smad3 or inhibition of Smad4 leads to the "switch" of TGF-β from a repressor to an activator. Down-regulation and abnormal cellular distribution of Smad4 were associated with some ERα-positive infiltrating human breast carcinoma. There appears a dynamic change of Smad4 expression from benign breast ductal tissue to infiltrating ductal carcinoma.

Conclusion

These results suggest that aberrant expression of Smad4 or disruption of Smad4 activity lead to the loss of TGF-β suppression of ERα transactivity in breast cancer cells.
Appendix
Available only for authorised users
Literature
1.
Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA: Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007, 87: 905-931. 10.1152/physrev.00026.2006CrossRefPubMed
2.
Speirs V, Walker RA: New perspectives into the biological and clinical relevance of oestrogen receptors in the human breast. J Pathol. 2007, 211: 499-506. 10.1002/path.2130CrossRefPubMed
3.
4.
Holst F, Stahl PR, Ruiz C, Hellwinkel O, Jehan Z, Wendland M, Lebeau A, Terracciano L, Al-Kuraya K, Janicke F: Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat Genet. 2007, 39: 655-660. 10.1038/ng2006CrossRefPubMed
5.
Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN: Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995, 13: 513-529.PubMed
6.
Yamashita H, Nishio M, Kobayashi S, Ando Y, Sugiura H, Zhang Z, Hamaguchi M, Mita K, Fujii Y, Iwase H: Phosphorylation of estrogen receptor alpha serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer. Breast Cancer Res. 2005, 7: R753-764. 10.1186/bcr1285PubMedCentralCrossRefPubMed
7.
Arrick BA, Korc M, Derynck R: Differential regulation of expression of three transforming growth factor beta species in human breast cancer cell lines by estradiol. Cancer Res. 1990, 50: 299-303.PubMed
8.
Jeng MH, ten Dijke P, Iwata KK, Jordan VC: Regulation of the levels of three transforming growth factor beta mRNAs by estrogen and their effects on the proliferation of human breast cancer cells. Mol Cell Endocrinol. 1993, 97: 115-123. 10.1016/0303-7207(93)90217-8CrossRefPubMed
9.
Feng XH, Derynck R: Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005, 21: 659-693. 10.1146/annurev.cellbio.21.022404.142018CrossRefPubMed
10.
Pasche B, Knobloch TJ, Bian Y, Liu J, Phukan S, Rosman D, Kaklamani V, Baddi L, Siddiqui FS, Frankel W: Somatic acquisition and signaling of TGFBR1*6A in cancer. Jama. 2005, 294: 1634-1646. 10.1001/jama.294.13.1634CrossRefPubMed
11.
Seoane J: Escaping from the TGFbeta anti-proliferative control. Carcinogenesis. 2006, 27: 2148-2156. 10.1093/carcin/bgl068CrossRefPubMed
12.
Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M: Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene. 1999, 18: 4879-4883. 10.1038/sj.onc.1202866CrossRefPubMed
13.
14.
Chang CF, Westbrook R, Ma J, Cao D: Transforming growth factor-beta signaling in breast cancer. Front Biosci. 2007, 12: 4393-4401. 10.2741/2396CrossRefPubMed
15.
Muraoka-Cook RS, Dumont N, Arteaga CL: Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin Cancer Res. 2005, 11: 937s-943s.PubMed
16.
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: 1643-1657. 10.1210/me.2003-0278CrossRefPubMed
17.
Buck MB, Knabbe C: TGF-beta signaling in breast cancer. Ann N Y Acad Sci. 2006, 1089: 119-126. 10.1196/annals.1386.024CrossRefPubMed
18.
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. 10.1002/(SICI)1097-4644(19960401)61:1<9::AID-JCB2>3.0.CO;2-ZCrossRefPubMed
19.
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: 42908-42914. 10.1074/jbc.M105316200CrossRefPubMed
20.
Paez-Pereda M, Giacomini D, Refojo D, Nagashima AC, Hopfner U, Grubler Y, Chervin A, Goldberg V, Goya R, Hentges ST: Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk. Proc Natl Acad Sci USA. 2003, 100: 1034-1039. 10.1073/pnas.0237312100PubMedCentralCrossRefPubMed
21.
Wu L, Wu Y, Gathings B, Wan M, Li X, Grizzle W, Liu Z, Lu C, Mao Z, Cao X: Smad4 as a transcription corepressor for estrogen receptor alpha. J Biol Chem. 2003, 278: 15192-15200. 10.1074/jbc.M212332200CrossRefPubMed
22.
Yamamoto T, Saatcioglu F, Matsuda T: Cross-talk between bone morphogenic proteins and estrogen receptor signaling. Endocrinology. 2002, 143: 2635-2642. 10.1210/en.143.7.2635CrossRefPubMed
23.
Chen CR, Kang Y, Siegel PM, Massague J: E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell. 2002, 110: 19-32. 10.1016/S0092-8674(02)00801-2CrossRefPubMed
24.
Bonni S, Wang HR, Causing CG, Kavsak P, Stroschein SL, Luo K, Wrana JL: TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol. 2001, 3: 587-595. 10.1038/35078562CrossRefPubMed
25.
Pouliot F, Labrie C: Expression profile of agonistic Smads in human breast cancer cells: absence of regulation by estrogens. Int J Cancer. 1999, 81: 98-103. 10.1002/(SICI)1097-0215(19990331)81:1<98::AID-IJC17>3.0.CO;2-9CrossRefPubMed
26.
Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, La Starza R, Diverio D, Colombo E, Santucci A: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005, 352: 254-266. 10.1056/NEJMoa041974CrossRefPubMed
27.
Koch S, Jacobi A, Ryser M, Ehninger G, Thiede C: Abnormal localization and accumulation of FLT3-ITD, a mutant receptor tyrosine kinase involved in leukemogenesis. Cells Tissues Organs. 2008, 188: 225-235. 10.1159/000118788CrossRefPubMed
28.
Murata T, Naomoto Y, Yamatsuji T, Okawa T, Shirakawa Y, Gunduz M, Nobuhisa T, Takaoka M, Sirmali M, Nakajima M: Localization of FAK is related with colorectal carcinogenesis. Int J Oncol. 2008, 32: 791-796.PubMed
29.
Sbalchiero E, Azzalin A, Palumbo S, Barbieri G, Arias A, Simonelli L, Ferretti L, Comincini S: Altered cellular distribution and sub-cellular sorting of doppel (Dpl) protein in human astrocytoma cell lines. Cell Oncol. 2008, 30: 337-347.PubMed
30.
Xie W, Mertens JC, Reiss DJ, Rimm DL, Camp RL, Haffty BG, Reiss M: Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Cancer Res. 2002, 62: 497-505.PubMed
31.
Wu G, Fan RS, Li W, Srinivas V, Brattain MG: Regulation of transforming growth factor-beta type II receptor expression in human breast cancer MCF-7 cells by vitamin D3 and its analogues. J Biol Chem. 1998, 273: 7749-7756. 10.1074/jbc.273.13.7749CrossRefPubMed
32.
Bleeker FE, Lamba S, Rodolfo M, Scarpa A, Leenstra S, Vandertop WP, Bardelli A: Mutational profiling of cancer candidate genes in glioblastoma, melanoma and pancreatic carcinoma reveals a snapshot of their genomic landscapes. Hum Mutat. 2009, 30: E451-459. 10.1002/humu.20927CrossRefPubMed
33.
Miyaki M, Kuroki T: Role of Smad4 (DPC4) inactivation in human cancer. Biochem Biophys Res Commun. 2003, 306: 799-804. 10.1016/S0006-291X(03)01066-0CrossRefPubMed
34.
Seshimo I, Yamamoto H, Mishima H, Kurata A, Suzuki R, Ezumi K, Takemasa I, Ikeda M, Fukushima T, Tsujinaka T: Expression and mutation of SMAD4 in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum. J Exp Clin Cancer Res. 2006, 25: 433-442.PubMed
35.
Yang L, Wang N, Tang Y, Cao X, Wan M: Acute myelogenous leukemia-derived SMAD4 mutations target the protein to ubiquitin-proteasome degradation. Hum Mutat. 2006, 27: 897-905. 10.1002/humu.20387CrossRefPubMed
36.
Jakob J, Nagase S, Gazdar A, Chien M, Morozova I, Russo JJ, Nandula SV, Murty VV, Li CM, Tycko B, Parsons R: Two somatic biallelic lesions within and near SMAD4 in a human breast cancer cell line. Genes Chromosomes Cancer. 2005, 42: 372-383. 10.1002/gcc.20142CrossRefPubMed
37.
Zhong D, Morikawa A, Guo L, Colpaert C, Xiong L, Nassar A, Chen C, Lamb N, Dong JT, Zhou W: Homozygous deletion of SMAD4 in breast cancer cell lines and invasive ductal carcinomas. Cancer Biol Ther. 2006, 5: 601-607. 10.4161/cbt.5.6.2660CrossRefPubMed
38.
Li W, Qiao W, Chen L, Xu X, Yang X, Li D, Li C, Brodie SG, Meguid MM, Hennighausen L, Deng CX: Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice. Development. 2003, 130: 6143-6153. 10.1242/dev.00820CrossRefPubMed
39.
Colombo E, Martinelli P, Zamponi R, Shing DC, Bonetti P, Luzi L, Volorio S, Bernard L, Pruneri G, Alcalay M, Pelicci PG: Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant. Cancer Res. 2006, 66: 3044-3050. 10.1158/0008-5472.CAN-05-2378CrossRefPubMed
40.
Lindstrom MS, Zhang Y: B23 and ARF: friends or foes?. Cell Biochem Biophys. 2006, 46: 79-90. 10.1385/CBB:46:1:79CrossRefPubMed
41.
Aitchison AA, Veerakumarasivam A, Vias M, Kumar R, Hamdy FC, Neal DE, Mills IG: Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. Prostate. 2008, 68: 661-674. 10.1002/pros.20730CrossRefPubMed
42.
Leng A, Liu T, He Y, Li Q, Zhang G: Smad4/Smad7 balance: A role of tumorigenesis in gastric cancer. Exp Mol Pathol. 2009
43.
Stuelten CH, Buck MB, Dippon J, Roberts AB, Fritz P, Knabbe C: Smad4-expression is decreased in breast cancer tissues: a retrospective study. BMC Cancer. 2006, 6: 25- 10.1186/1471-2407-6-25PubMedCentralCrossRefPubMed
44.
Xu WQ, Jiang XC, Zheng L, Yu YY, Tang JM: Expression of TGF-beta1, TbetaRII and Smad4 in colorectal carcinoma. Exp Mol Pathol. 2007, 82: 284-291. 10.1016/j.yexmp.2006.10.011CrossRefPubMed
Metadata
Title
Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer
Authors
Yongsheng Ren
Liyu Wu
Andra R Frost
William Grizzle
Xu Cao
Mei Wan
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2009
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-8-111

Other articles of this Issue 1/2009

Molecular Cancer 1/2009 Go to the issue

Research

Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis

Research

Blockage of transdifferentiation from fibroblast to myofibroblast in experimental ovarian cancer models

Research

Aurora-A down-regulates IkappaBα via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival

Short communication

No effect of cancer-associated SNP rs6983267 in the 8q24 region on co-expression of MYC and TCF7L2 in normal colon tissue

Research

Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

Research

Genomic imbalances in precancerous tissues signal oral cancer risk
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits